Phosphodiesterase 4 inhibitors

ABSTRACT

PDE4 inhibition is achieved by novel compounds of the Formula I: 
                         
wherein R 1  and R 2  are as defined herein.

This application claims benefit of U.S. Provisional application Ser. No.60/267,195, filed Feb. 8, 2001, and U.S. Provisional application Ser.No. 60/344,824, filed Jan. 7, 2002.

FIELD OF THE INVENTION

The present invention relates generally to the field ofphosphodiesterase 4 (PDE4) enzyme inhibition. More specifically thisinvention relates to selective PDE4 inhibition by novel adenine analogs,methods of preparing such compounds, compositions containing suchcompounds, and methods of use thereof.

BACKGROUND OF THE INVENTION

The cyclic nucleotide specific phosphodiesterases (PDEs) represent afamily of enzymes that catalyze the hydrolysis of various cyclicnucleoside monophosphates (including cAMP and cGMP). These cyclicnucleotides act as second messengers within cells, and as messengers,carry impulses from cell surface receptors having bound various hormonesand neurotransmitters. PDEs act to regulate the level of cyclicnucleotides within cells and maintain cyclic nucleotide homeostasis bydegrading such cyclic mononucleotides resulting in termination of theirmessenger role.

PDE enzymes can be grouped into eleven families according to theirspecificity toward hydrolysis of cAMP or cGMP, their sensitivity toregulation by calcium, calmodulin or cGMP, and their selectiveinhibition by various compounds. For example, PDE 1 is stimulated byCa²⁺/calmodulin. PDE 2 is cGMP-dependent, and is found in the heart andadrenals. PDE 3 is cGMP-dependent, and inhibition of this enzyme createspositive inotropic activity. PDE 4 is cAMP specific, and its inhibitioncauses airway relaxation, antiinflammatory and antidepressant activity.PDE 5 appears to be important in regulating cGMP content in vascularsmooth muscle, and therefore PDE 5 inhibitors may have cardiovascularactivity. Since the PDEs possess distinct biochemical properties, it islikely that they are subject to a variety of different forms ofregulation.

PDE4 is distinguished by various kinetic properties including lowMichaelis constant for cAMP and sensitivity to certain drugs. The PDE4enzyme family consists of four genes, which produce 4 isoforms of thePDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [See: Wang et al.,Expression, Purification, and Characterization of human cAMP-SpecificPhosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Res.Comm., 234, 320-324 (1997)] In addition, various splice variants of eachPDE4 isoform have been identified.

PDE4 isoenzymes are localized in the cytosol of cells and areunassociated with any known membranous structures. PDE4 isoenzymesspecifically inactivate cAMP by catalyzing its hydrolysis to adenosine5′-monophosphate (AMP). Regulation of cAMP activity is important in manybiological processes, including inflammation and memory. Inhibitors ofPDE4 isoenzymes such as rolipram, piclamilast, CDP-840 and ariflo arepowerful antiinflammatory agents and therefore may be useful in treatingdiseases where inflammation is problematic such as asthma or arthritis.Further, rolipram improves the cognitive performance of rats and mice inlearning paradigms.

In addition to such compounds as rolipram, xanthine derivatives such aspentoxifylline, denbufylline, and theophylline inhibit PDE4 and havereceived considerable attention of late for their cognition enhancingeffects. cAMP and cGMP are second messengers that mediate cellularresponses to many different hormones and neurotransmitters. Thus,therapeutically significant effects may result from PDE inhibition andthe resulting increase in intracellular cAMP or cGMP in key cells, suchas those located in the nervous system and elsewhere in the body.

Rolipram, previously in development as an anti-depressant, selectivelyinhibits the PDE4 enzyme and has become a standard agent in theclassification of PDE enzyme subtypes. Early work in the PDE4 fieldfocused on depression and inflammation, and has subsequently beenextended to include indications such as dementia. [see “The PDE IVFamily Of Calcium-Phosphodiesterases Enzymes,” John A. Lowe, III, etal., Drugs of the Future 1992, 17(9):799-807 for a general review).Further clinical developments of rolipram and other first-generationPDE4 inhibitors were terminated due to the side effect profile of thesecompounds. The primary side effect in primates is emesis, while theprimary side effects in rodents are testicular degranulation, weakeningof vascular smooth muscle, psychotrophic effects, increased gastric acidsecretion and stomach erosion.

SUMMARY OF THE INVENTION

The present invention relates to novel adenine compounds that inhibitPDE4 enzymes, and especially have improved side effect profiles, e.g.,are relatively non-emetic, (e.g., as compared to the previouslydiscussed prior art compounds). In particular, the present inventionrelates to novel 9-substituted-2-trifluoromethyladenine compounds thatpossess PDE4 inhibitory activity. Preferably, the compounds selectivelyinhibit PDE4 enzymes. The compounds of this invention at the same timefacilitate entry into cells, especially cells of the nervous system.

Still further, the present invention provides methods for synthesizingcompounds with such activity and selectivity as well as methods of (andcorresponding pharmaceutical compositions for) treating a patient, e.g.,mammals, including humans, requiring PDE inhibition, especially PDE4inhibition, for a disease state that involves elevated intracellular PDE4 levels or decreased cAMP levels, e.g., involving neurologicalsyndromes, especially those states associated with memory impairment,most especially long term memory impairment, as where such memoryimpairment is due in part to catabolism of intracellular cAMP levels byPDE 4 enzymes, or where such memory impairment may be improved byeffectively inhibiting PDE4 enzyme activity.

In a preferred aspect, the compounds of the invention improve suchdiseases by inhibiting PDE4 enzymes at doses which do not induce emesis.

Upon further study of the specification and appended claims, furtheraspects, objects and advantages of this invention will become apparentto those skilled in the art.

The present invention includes compounds of Formula I:

wherein,

-   R¹ is H,    -   alkyl having 1 to 5 carbon atoms, which is unsustituted or        substituted one or more times by halogen, hydroxy, or        combinations thereof, and wherein a —CH₂— group can be        optionally replaced by —O—, —S—, or —NH—,    -   cycloalkyl having 3 to 6 carbon atoms, or    -   cycloalkylalkyl having 4 to 7 C atoms;-   R² is alkyl having 1 to 12 carbon atoms, which is unsubstituted or    substituted one or more times by halogen, hydroxy, cyano or    combinations thereof, wherein one or more —CH₂— groups is each    independently optionally replaced by —O—, —S—, or —NH—, and wherein    optionally one or more —CH₂CH₂— groups is replaced in each case by    —CH═CH— or —C≡C—,    -   alkyl ether having 3 to 12 carbon atoms,    -   cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted        or substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or combinations        thereof,    -   cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted        or substituted one or more times by C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, C₁₋₄ alkoxy, cyano, halogen, or combinations thereof,    -   aryl having 6 to 14 carbon atoms, which is unsubstituted or        substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or        substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   heteroaryl having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or substituted one        or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,        carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,        C₁₋₄-alkylsulphonyl, or combinations thereof,    -   heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring        atoms in which at least 1 ring atom is a heteroatom and the        alkyl portion has 1 to 3 carbon atoms, the heteroaryl portion is        unsubstituted or is substituted one or more times in by halogen,        aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,        halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo,        amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,        alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations        thereof,    -   heterocycle having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or is substituted        one or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations        thereof (e.g., piperidinyl, imidazolinyl, imidazolidinyl,        pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl, and        indolinyl),    -   heterocycle-alkyl wherein the heterocycle portion has 5 to 10        ring atoms in which at least 1 ring atom is a heteroatom and the        alkyl portion has 1 to 3 carbon atoms, the heterocycle portion        is nonarmoatic and is unsubstituted or is substituted one or        more times in the by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations        thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or    -   carbocycle which is nonaromatic, monocyclic or bicyclic, group        having 5 to 14 carbon atoms, which is unsubstituted or is        substituted one or more times in the by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylmedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof;    -   and    -   pharmaceutically acceptable salts thereof,    -   with the provisos that:        -   (a) when R¹ is methyl, then R² is not arylalkyl,            heteroarylalkyl, 2-(1,2,3,4-tetrahydro)quinolinyl-methyl,            methyl or 2-butyl;        -   (b) when R¹ is cyclopropyl, R² is not 4-methylbenzyl;        -   (c) when R¹ is ethyl, then R² is not ethyl, 3-aminobenzyl,            2-thienylmethyl, 3-thienylmethyl, or 2-pyridylmethyl;        -   (d) when R¹ is cyclopropyl, then R² is not            cyclopropylmethyl;        -   (e) when R¹ is H, then R² is not methyl, ethyl, benzyl,            4-methylbenzyl, or substituted tetrahydrofuranyl;        -   (f) when R¹ is methoxyethyl, then R² is not benzyl,            3-dimethylaminobenzyl, or 3-thienylmethyl;        -   (g) when R¹ is iso-butyl, then R² is not benzyl; and        -   (h) when R¹ is n-butyl, then R² is not n-butyl.

According to a further aspect of the invention there is provided a genusaccording to formula I wherein when R¹ is methyl, R² is not arylalkyl,heteroarylalkyl, 2-(1,2,3,4-tetrahydro)quinolinyl-methyl or C₁₋₅-alkyl.

According to a further aspect of the invention there is provided a genusaccording to formula I wherein when R¹ is methyl, R² is not arylalkyl,heteroarylalkyl, heterocyclealkyl or C₁₋₅-alkyl.

According to a further aspect of the invention there is provided a genusaccording to formula I wherein when R¹ is cyclopropyl, R² is notarylalkyl.

According to a further aspect of the invention there is provided a genusaccording to formula I wherein when R¹ is ethyl, R² is not arylalkyl,heteroarylalkyl, or C₁₋₃-alkyl.

According to a further aspect of the invention there is provided a genusaccording to formula I wherein when R¹ is cyclopropyl, R² is notcycloalkylalkyl.

According to a further aspect of the invention there is provided a genusaccording to formula I wherein when R¹ is H, R² is not arylalkyl,heterocycle or C₁₋₃-alkyl.

According to a further aspect of the invention there is provided a genusaccording to formula I wherein when R¹ is methoxyethyl, R² is notarylalkyl or heteroarylalkyl.

According to a further aspect of the invention there is provided a genusaccording to formula I wherein when R¹ is a butyl group, R² is notarylalkyl or C₁₋₅-alkyl.

According to a preferred aspect of the invention there is provided agenus of novel compounds according to formula II

wherein

-   R^(1′) is methyl, ethyl, or cyclopropyl; and-   R^(2′) is cycloalkyl having 3 to 12 carbon atoms, which is    unsubstituted or substituted one or more times by halogen, C₁₋₄    alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or combinations    thereof,    -   aryl having 6 to 14 carbon atoms, which is unsubstituted or        substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   heteroaryl having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or substituted one        or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,        carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,        C₁₋₄-alkylsulphonyl, or combinations thereof,    -   heterocycle having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or is substituted        one or more times in the by halogen, aryl, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,        C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or        combinations thereof (e.g., piperidinyl, imidazolinyl,        imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,        piperazinyl, and indolinyl), or    -   carbocycle which is nonaromatic, monocyclic or bicyclic, group        having 5 to 14 carbon atoms, which is unsubstituted or is        substituted one or more times in the by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof;    -   and    -   pharmaceutically acceptable salts thereof.

According to a further aspect of the invention there is provided a genusof novel compounds according to the Formula III:

wherein

-   R^(1″) is H,    -   alkyl having 1 to 5 carbon atoms,    -   alkyl having 1 to 5 carbon atoms which is substituted one or        more times by halogen, hydroxy, oxo, cyano or combinations        thereof,    -   cycloalkyl having 3 to 6 carbon atoms,    -   cycloalkyl having 3 to 6 carbon atoms, which is substituted one        or more times by halogen, alkyl, oxo or combinations thereof,    -   cycloalkylalkyl having 4 to 7 C atoms,    -   cycloalkylalkyl having 4 to 7 C atoms, which is substituted one        or more times by C₁₋₄ alkyl, halogen, halogenated C₁₋₄ alkyl, or        combinations thereof,-   R^(2″) is alkyl having 1 to 12 carbon atoms,    -   alkyl having 1 to 12 carbon atoms which is substituted one or        more times by halogen, hydroxy, oxo, cyano or combinations        thereof,    -   alkyl ether having 3 to 12 carbon atoms,    -   cycloalkyl having 3 to 12 carbon atoms,    -   cycloalkyl having 3 to 12 carbon atoms which is substituted one        or more times by halogen, C₁₋₄ alkyl, oxo or combinations        thereof,    -   cycloalkylalkyl having 4 to 12 C atoms,    -   cycloalkylalkyl having 4 to 12 C atoms, which is substituted one        or more times by C₁₋₄ alkyl, halogen, halogenated C₁₋₄ alkyl, or        combinations thereof,    -   aryl having 6 to 10 carbon atoms,    -   aryl having 6 to 10 carbon atoms which is substituted one or        more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,        hydroxy, C₁₋₄-alkoxy, nitro, methylenedioxy, ethylenedioxy,        amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄, acyl,        C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,        C₁₋₄-alkylsulphonyl, phenoxy, or combinations thereof,    -   arylalkyl having 7 to 16 carbon atoms,    -   arylalkyl having 7 to 16 carbon atoms which is substituted one        or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,        hydroxy, C₁₋₄-alkoxy, nitro, methylenedioxy, ethylenedioxy,        amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄, acyl,        C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,        C₁₋₄-alkylsulphonyl, phenoxy, or combinations thereof,    -   heteroaryl having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom,    -   substituted heteroaryl having 5 to 10 ring atoms, in which at        least 1 ring atom is a heteroatom, which is substituted one or        more times by halogen, aryl, C₁₋₄-alkyl, C₁₋₄-alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino or combinations thereof,    -   heteroarylalkyl having 5 to 10 ring atoms in which at least 1        ring atom is a heteroatom, or    -   substituted heteroarylalkyl having 5 to 10 ring atoms in which        at least 1 ring atom is a heteroatom and which is substituted        one or more times in the heteroaryl portion by halogen, aryl,        C₁₋₄-alkyl, C₁₋₄-alkoxy, cyano, trifluoromethyl, nitro, oxo,        amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino or combinations        thereof and/or substituted in the alkyl portion by halogen, oxo,        cyano, or combinations thereof;    -   and    -   pharmaceutically acceptable salts thereof,    -   with the provisos that    -   (a) when R^(1″) is methyl, then R^(2″) is not arylalkyl,        heteroarylalkyl, methyl or 2-butyl,    -   (b) when R^(1″) is cyclopropyl, R^(2″) is not 4-methylbenzyl,    -   (c) when R^(1″) is ethyl, then R^(2″) is not ethyl, and    -   (d) when R^(1″) is cyclopropyl, then R^(2″) is not        cyclopropylmethyl.

In accordance with a further aspect of the invention, there is provideda genus of formula III in which R^(1″) and R^(2″) are in accordance withthe following subformulas:

-   -   IIIa R^(1″) is cyclopropyl; and        -   R^(2″) is cycloalkyl.    -   IIIb R^(1″) is methyl; and        -   R^(2″) is cycloalkyl.    -   IIIc R^(1″) is methyl, ethyl, cyclopropyl; and        -   R^(2″) is phenyl or substituted phenyl.    -   IIId R^(1″) is methyl, ethyl, cyclopropyl; and        -   R^(2″) is heteroaryl or substituted heteroaryl.

The compounds of the present invention are effective in inhibiting, ormodulating the activity of PDE4 in animals, e.g., mammals, especiallyhumans. These compounds exhibit neurological activity, especially wheresuch activity affects cognition, including long term memory. Thesecompounds will also be effective in treating diseases where decreasedcAMP levels are involved. This includes but is not limited toinflammatory diseases. These compounds may also function asantidepressants, or be useful in treating cognitive and negativesymptoms of schizophrenia.

In accordance with the method aspect of the invention, there is provideda method of treating a patient (e.g., a mammal such as a human)suffering from a disease state (e.g., memory impairment, inflammatorydisesases, depression, etc.) involving decreased cAMP levels and/orincreased intracellular PDE4 levels, comprising administering to thepatient a compound according to formula I^(a):

wherein,

-   R^(1a) is H,    -   alkyl having 1 to 5 carbon atoms, which is unsustituted or        substituted one or more times by halogen, hydroxy, or        combinations thereof, and wherein a —CH₂— group can be        optionally replaced by —O—, —S—, or —NH—,    -   cycloalkyl having 3 to 6 carbon atoms, or    -   cycloalkylalkyl having 4 to 7 C atoms;-   R^(2a) is alkyl having 1 to 12 carbon atoms, which is unsubstituted    or substituted one or more times by halogen, hydroxy, cyano or    combinations thereof, wherein one or more —CH₂— groups is each    independently optionally replaced by —O—, —S—, or —NH—, and wherein    optionally one or more —CH₂CH₂— groups is replaced in each case by    —CH═CH— or —C≡C—    -   alkyl ether having 3 to 12 carbon atoms,    -   cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted        or substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or combinations        thereof,    -   cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted        or substituted one or more times by C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, C₁₋₄ alkoxy, cyano, halogen, or combinations thereof,    -   aryl having 6 to 14 carbon atoms, which is unsubstituted or        substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or        substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   heteroaryl having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or substituted one        or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,        carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,        C₁₋₄-alkylsulphonyl, or combinations thereof,    -   heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring        atoms in which at least 1 ring atom is a heteroatom and the        alkyl portion has 1 to 3 carbon atoms, the heteroaryl portion is        unsubstituted or is substituted one or more times in by halogen,        aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,        halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo,        amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,        alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations        thereof,    -   heterocycle having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or is substituted        one or more times in the by halogen, aryl, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,        C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or        combinations thereof (e.g., piperidinyl, imidazolinyl,        imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,        piperazinyl, and indolinyl),    -   heterocycle-alkyl wherein the heterocycle portion has 5 to 10        ring atoms in which at least 1 ring atom is a heteroatom and the        alkyl portion has 1 to 3 carbon atoms, the heterocycle portion        is nonarmoatic and is unsubstituted or is substituted one or        more times in the by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations        thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or    -   carbocycle which is nonaromatic, monocyclic or bicyclic, group        having 5 to 14 carbon atoms, which is unsubstituted or is        substituted one or more times in the by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof;    -   and    -   pharmaceutically acceptable salts thereof,    -   with the provisos that:        -   (a) when R^(1a) is methyl, then R^(2a) is not arylalkyl,            heteroarylalkyl, 2-(1,2,3,4-tetrahydro)quinolinyl-methyl,            methyl or 2-butyl;        -   (b) when R^(1a) is cyclopropyl, R^(2a) is not            4-methylbenzyl;        -   (c) when R^(1a) is ethyl, then R^(2a) is not ethyl,            3-aminobenzyl, 2-thienylmethyl, 3-thienylmethyl, or            2-pyridylmethyl;        -   (d) when R^(1a) is cyclopropyl, then R^(2a) is not            cyclopropylmethyl;        -   (e) when R^(1a) is H, then R^(2a) is not methyl, ethyl,            benzyl, 4-methylbenzyl, or substituted tetrahydrofuranyl;        -   (f) when R^(1a) is methoxyethyl, then R^(2a) is not benzyl,            3-dimethylaminobenzyl, or 3-thienyhnethyl;        -   (g) when R^(1a) is iso-butyl, then R^(2a) is not benzyl; and        -   (h) when R^(1a) is n-butyl, then R^(2a) is not n-butyl.

In accordance with the method aspect of the invention, there is provideda method of treating a patient (e.g., a mammal such as a human)suffering from a disease state (e.g., memory impairment) involvingdecreased cAMP levels and/or increased intracellular PDE4 levels,comprising administering to the patient a compound according to formulaI^(b):

wherein,

-   R^(1b) is H,    -   alkyl having 1 to 5 carbon atoms, which is unsustituted or        substituted one or more times by halogen, hydroxy, or        combinations thereof, and wherein a —CH₂— group can be        optionally replaced by —O—, —S—, or —NH—,    -   cycloalkyl having 3 to 6 carbon atoms, or    -   cycloalkylalkyl having 4 to 7 C atoms;-   R^(2b) is alkyl having 1 to 12 carbon atoms, which is unsubstituted    or substituted one or more times by halogen, hydroxy, cyano or    combinations thereof, wherein one or more —CH₂— groups is each    independently optionally replaced by —O—, —S—, or —NH—, and wherein    optionally one or more —CH₂CH₂— groups is replaced in each case by    —CH═CH— or —C≡C—    -   alkyl ether having 3 to 12 carbon atoms,    -   cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted        or substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or combinations        thereof,    -   cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted        or substituted one or more times by C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, C₁₋₄ alkoxy, cyano, halogen, or combinations thereof,    -   aryl having 6 to 14 carbon atoms, which is unsubstituted or        substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or        substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   heteroaryl having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or substituted one        or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,        carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,        C₁₋₄-alkylsulphonyl, or combinations thereof,    -   heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring        atoms in which at least 1 ring atom is a heteroatom and the        alkyl portion has 1 to 3 carbon atoms, the heteroaryl portion is        unsubstituted or is substituted one or more times in by halogen,        aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,        halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo,        amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,        alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations        thereof,    -   heterocycle having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or is substituted        one or more times in the by halogen, aryl, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,        C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or        combinations thereof (e.g., piperidinyl, imidazolinyl,        imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,        piperazinyl, and indolinyl),    -   heterocycle-alkyl wherein the heterocycle portion has 5 to 10        ring atoms in which at least 1 ring atom is a heteroatom and the        alkyl portion has 1 to 3 carbon atoms, the heterocycle portion        is nonarmoatic and is unsubstituted or is substituted one or        more times in the by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations        thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or    -   carbocycle which is nonaromatic, monocyclic or bicyclic, group        having 5 to 14 carbon atoms, which is unsubstituted or is        substituted one or more times in the by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof;    -   and    -   pharmaceutically acceptable salts thereof,    -   with the provisos that when R^(1b) is methyl, then R^(2b) is not        arylalkyl, methyl or 2-butyl, and when R^(1b) is H, then R^(2b)        is not benzyl.

In accordance with a further method aspect of the invention, there isprovided a method of treating a patient (e.g., a mammal such as a human)suffering from a disease state (e.g., memory impairment) involvingdecreased cAMP levels and/or increased intracellular PDE4 levels,comprising administering to the patient a compound according to formulaI^(c):

wherein,

-   R^(1c) is H,    -   alkyl having 1 to 5 carbon atoms, which is unsustituted or        substituted one or more times by halogen, hydroxy, or        combinations thereof, and wherein a —CH₂— group can be        optionally replaced by —O—, —S—, or —NH—,    -   cycloalkyl having 3 to 6 carbon atoms, or    -   cycloalkylalkyl having 4 to 7 C atoms;-   R^(2c) is alkyl having 1 to 12 carbon atoms, which is unsubstituted    or substituted one or more times by halogen, hydroxy, cyano or    combinations thereof, wherein one or more —CH₂— groups is each    independently optionally replaced by —O—, —S—, or —NH—, and wherein    optionally one or more —CH₂CH₂— groups is replaced in each case by    —CH═CH— or —C≡C—    -   alkyl ether having 3 to 12 carbon atoms,    -   cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted        or substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or combinations        thereof,    -   cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted        or substituted one or more times by C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, C₁₋₄ alkoxy, cyano, halogen, or combinations thereof,    -   aryl having 6 to 14 carbon atoms, which is unsubstituted or        substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or        substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   heteroaryl having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or substituted one        or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,        carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,        C₁₋₄-alkylsulphonyl, or combinations thereof,    -   heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring        atoms in which at least 1 ring atom is a heteroatom and the        alkyl portion has 1 to 3 carbon atoms, the heteroaryl portion is        unsubstituted or is substituted one or more times in by halogen,        aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,        halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro, oxo,        amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,        alkoxycarbonyl, hydroxamic acid, carboxamide, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations        thereof,    -   heterocycle having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or is substituted        one or more times in the by halogen, aryl, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,        C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or        combinations thereof (e.g., piperidinyl, imidazolinyl,        imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,        piperazinyl, and indolinyl),    -   heterocycle-alkyl wherein the heterocycle portion has 5 to 10        ring atoms in which at least 1 ring atom is a heteroatom and the        alkyl portion has 1 to 3 carbon atoms, the heterocycle portion        is nonarmoatic and is unsubstituted or is substituted one or        more times in the by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations        thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or    -   carbocycle which is nonaromatic, monocyclic or bicyclic, group        having 5 to 14 carbon atoms, which is unsubstituted or is        substituted one or more times in the by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof;    -   and    -   pharmaceutically acceptable salts thereof,    -   with the proviso that said compound is not        6-methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine.

In accordance with a further method aspect of the invention, there isprovided a method of treating a patient (e.g., a mammal such as a human)suffering from a disease state (e.g., memory impairment) involvingdecreased cAMP levels and/or increased intracellular PDE4 levels,comprising administering to the patient a compound according to formulaII

wherein

R^(1′) is methyl, ethyl, or cyclopropyl; and

-   R^(2′) is cycloalkyl having 3 to 12 carbon atoms, which is    unsubstituted or substituted one or more times by halogen, C₁₋₄    alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or combinations    thereof,    -   aryl having 6 to 14 carbon atoms, which is unsubstituted or        substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   heteroaryl having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or substituted one        or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄        alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,        trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,        di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid,        carboxamide, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,        C₁₋₄-alkylsulphonyl, or combinations thereof,    -   heterocycle having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, which is unsubstituted or is substituted        one or more times in the by halogen, aryl, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,        C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or        combinations thereof (e.g., piperidinyl, imidazolinyl,        imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl,        piperazinyl, and indolinyl), or    -   carbocycle which is nonaromatic, monocyclic or bicyclic, group        having 5 to 14 carbon atoms, which is unsubstituted or is        substituted one or more times in the by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄        alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄        alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,        C₁₋₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid,        carboxamide, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof;    -   and    -   pharmaceutically acceptable salts thereof.

In accordance with a further method aspect of the invention, there isprovided a method of treating a patient (e.g., a mammal such as a human)suffering from a disease state (e.g., memory impairment) involvingdecreased cAMP levels and/or increased intracellular PDE4 levels,comprising administering to the patient a compound according to formulaIII^(a):

wherein,

-   R^(1′″) is H,    -   alkyl having 1 to 5 carbon atoms, which is unsustituted or is        substituted one or more times by halogen, hydroxy, oxo, cyano or        combinations thereof,    -   cycloalkyl having 3 to 6 carbon atoms, which is unsubstituted or        is substituted one or more times by halogen, alkyl, oxo or        combinations thereof, or    -   cycloalkylalkyl having 4 to 7 C atoms, which is unsubstituted or        is substituted one or more times by C₁₋₄ alkyl, halogen,        halogenated C₁₋₄ alkyl, or combinations thereof; and-   R^(2′″) is alkyl having 1 to 12 carbon atoms, which is unsubstituted    or which is substituted one or more times by halogen, hydroxy, oxo,    cyano or combinations thereof,    -   alkyl ether having 3 to 12 carbon atoms,    -   cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted        or which is substituted one or more times by halogen, C₁₋₄        alkyl, oxo or combinations thereof,    -   cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted        or is substituted one or more times by C₁₋₄ alkyl, halogen,        halogenated C₁₋₄ alkyl, or combinations thereof,    -   aryl having 6 to 10 carbon atoms, which is unsubstituted or is        substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, nitro,        methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,        di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy,        carboxy, cyano, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or        is substituted one or more times by halogen, C₁₋₄ alkyl,        halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, nitro,        methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,        di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy,        carboxy, cyano, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,        C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or        combinations thereof,    -   heteroaryl having 5 to 10 ring atoms in which at least 1 ring        atom is a heteroatom, substituted heteroaryl having 5 to 10 ring        atoms, in which at least 1 ring atom is a heteroatom, which is        substituted one or more times by halogen, aryl, C₁₋₄-alkyl,        C₁₋₄-alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,        C₁₋₄-alkylamino, di-C₁₋₄-alkylamino or combinations thereof, or    -   heteroarylalkyl having 5 to 10 ring atoms in which at least 1        ring atom is a heteroatom, which is unsubstituted or is        substituted one or more times in the heteroaryl portion by        halogen, aryl, C₁₋₄-alkyl, C₁₋₄-alkoxy, cyano, trifluoromethyl,        nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino or        combinations thereof and/or substituted in the alkyl portion by        halogen, oxo, cyano, or combinations thereof; and    -   pharmaceutically acceptable salts thereof,    -   with the proviso that    -   (a) when R^(1′″) is methyl, then R^(2′″) is not arylalkyl,        heteroarylalkyl, methyl or 2-butyl.

In formula III^(a), R^(1′″) is preferably methyl, ethyl or cyclopropyl.

Assays for determining PDE inhibiting activity as well as selectivity ofPDE 4 inhibiting activity and selectivity of inhibiting PDE 4 isoenzymesare known within the art. See, e.g., U.S. Pat. No. 6,136,821, thedisclosure of which is incorporated herein by reference.

Halogen herein refers to F, Cl, Br, and I. Preferred halogens are F andCl.

Alkyl, as a group or substituent per se or as part of a group orsubstituent (e.g., alkylamino, trialkylsilyloxy, aminoalkyl,hydroxyalkyl), means a straight-chain or branched-chain aliphatichydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8carbon atoms, especially 1 to 4 carbon atoms.

Alkyl radicals for R¹ have up to 5 carbon atoms, preferably 1 to 4carbon atoms, especially 1 to 3 carbon atoms. Suitable alkyl groups forR¹ include methyl, ethyl, propyl, isopropyl, butyl, isopropyl andpentyl. Other examples of suitable alkyl groups for R¹ include 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl and 1-ethylpropyl.

Alkyl radicals for R² have up to 12 carbon atoms, preferably 3 to 8carbon atoms, especially 3 to 6 carbon atoms. Suitable alkyl groups forR² include those listed above for R¹ as well as hexyl, heptyl, octyl,nonyl, decyl, undecyl, dodecyl, 1-, 2-, 3- or 4-methylpentyl,tert-butyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, ethylnethylpropyl, trimethylpropyl, methylhexyl,dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl, and thelike.

Substituted alkyl groups are alkyl groups as described above which aresubstituted in one or more positions by, for example, halogens, oxo,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄-alkoxy, and/or cyano. Halogensare preferred substituents, especially F and Cl.

Alkoxy groups means alkyl-O— groups in which the alkyl portion is inaccordance with the previous discussion. Suitable alkoxy groups aremethoxy, ethoxy, propoxy and butoxy, pentoxy, hexoxy, heptoxy, octoxyand trifluoromethoxy. Preferred alkoxy groups are methoxy and ethoxy.Similarly, alkoxycarbonyl means alkyl —O—CO— in which the alkyl portionis in accordance with the previous discussion. Examples includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, andtert-butoxycarbonyl.

Alkenyl refers to straight-chain or branched-chain aliphatic radicalscontaining 2 to 12 carbon atoms in which one or more —CH₂—CH₂—structures are each replaced by —CH═CH—. Suitable alkenyl groups areethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1-pentenyl,and 2-pentenyl.

Alkynyl refers to straight-chain or branched-chain aliphatic radicalscontaining 2 to 12 carbon atoms in which one or more —CH₂—CH₂—structures are each replaced by —C≡C—. Suitable alkynyl groups areethynyl, propynyl, 1-butynyl, and 2-butynyl.

Cycloalkyl means a monocyclic, bicyclic or tricyclic nonaromaticsaturated hydrocarbon radical. Cycloalkyl radicals for R¹ have 3 to 6carbon atoms, preferably 3 to 5 carbon atoms, especially 3 carbon atoms.Suitable cycloalkyl groups for R¹ include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Cycloalkyl radicals for R² have 3 to 12carbon atoms, preferably 3 to 10 carbon atoms, especially 4 to 8 carbonatoms. Suitable cycloalkyl groups for R² include those listed above forR¹ as well as cycloheptyl, cyclooctyl, cyclononyl, norbornyl, 1-decalin,adamant-1-yl, and adamant-2-yl. Other suitable cycloalkyl groups for R²include spiro[2,4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl,bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, and bicyclo[4.2.0]octyl.

The cycloalkyl group can be substituted. For example, it can besubstituted by halogens, C₁₋₄-alkyls, C₁₋₄-halogenated alkyls,C₁₋₄-alkoxy and/or cyano.

Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which thecycloalkyl and alkyl portions are in accordance with previousdiscussions. Suitable examples include cyclopropylmethyl andcyclopentylmethyl.

Alkyl ethers refer to C₃ to C₁₂ alkoxyalkyl radicals. Suitable alkylether groups include methoxyethyl, ethoxyethyl, and methoxypropyl.

Aryl, as a group or substituent per se or as part of a group orsubstituent, refers to an aromatic carbocyclic radical containing 6 to14 carbon atoms, preferably 6 to 12 carbon atoms, especially 6 to 10carbon atoms. Suitable aryl groups include phenyl, naphthyl andbiphenyl. Substituted aryl groups include the above-described arylgroups which are substituted one or more times by, for example, byhalogen, C₁₋₄-alkyl, C₁₋₄-halogenated alkyl, hydroxy, C₁₋₄-alkoxy,C₁₋₄-halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl and phenoxy.

Arylalkyl refers to an aryl-alkyl-radical in which the aryl and alkylportions are in accordance with the previous descriptions. Preferably,the aryl portion has 6 to 10 carbon atoms and the alkyl portion, whichis straight-chained or branched, has 1 to 6 carbon atoms, preferably 1to 3 carbon atoms. The aryl portion can be substituted by thesubstituents described above for aryl groups and the alkyl portion canbe substituted by oxo, halogens, cyano or combinations thereof. Suitableexamples include benzyl, 1-phenethyl, 2-phenethyl, phenpropyl,fluorobenzyl, chlorobenzyl, methoxybenzyl, methylbenzyl and cyanobenzyl.

Heteroaryl refers to an aromatic heterocyclic group having one or tworings and a total number of 5 to 10 ring atoms wherein at least one ofthe ring atoms is a heteroatom. Preferably, the heteroaryl groupcontains 1 to 3, especially 1 or 2, hetero-ring atoms which are selectedfrom N, O and S. Suitable heteroaryl groups include furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl,oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, benzofuranyl,isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl,indazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl,benzisothiazolyl, purinyl, benzopyranyl, quinolinyl, isoquinolinyl,cinnolinyl, quinazolinyl, naphthyridinyl, and benzoxazinyl, e.g.,2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl.

Substituted heteroaryl refers to the heteroaryl groups described abovewhich are substitued in one or more places by, for example, halogen,hydroxyl, aryl, alkyl, alkoxy, carboxy, methylene, cyano,trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino.

Heteroarylalkyl refers to a heteroaryl-alkyl-group wherein theheteroaryl and alkyl portions are in accordance with the previousdiscussions. Suitable examples are pyridylmethyl, thienylmethyl,pyrimidinylmethyl, pyrazinylmethyl, and isoquinolinylmethyl.

Heterocycles are non-aromatic cyclic groups containing at least onehetero-ring atom, preferably selected from N, S and O, for example,3-tetrahydrofuranyl, piperidinyl, imidazolinyl, imidazolidinyl,pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl, and indolinyl.

Heterocycle-alkyl refers to a heterocycle-alkyl-group wherein theheterocyclic and alkyl portions are in accordance with the previousdiscussions. Suitable examples are piperidinyl-ethyl andpyrrolinyl-methyl.

Carbocycles are non-aromatic monocyclic or bicyclic structurescontaining 5 to 14 carbon atoms, preferably 6 to 10 carbon atoms.Suitable examples are cyclopentenyl, cyclohexenyl, cyclohexadienyl,tetrahydronaphthenyl and indan-2-yl.

Acyl refers to alkanoyl radicals having 1 to 6 carbon atoms in which thealkyl portion can be substituted by halogen, alkyl, aryl and/or alkoxy,or aroyl radicals having 7 to 15 carbon atoms in which the aryl portioncan be substituted by, for example, halogen, alkyl and/or alkoxy.Suitable acyl groups include formyl, acetyl, propionyl, butanoyl andbenzoyl.

Substituted radicals preferably have 1 to 3 substituents, especially 1to 2 substituents.

R¹ is preferably H, alkyl such as methyl, ethyl and isopropyl,substituted alkyl, such as HOCH₂CH₂—, cycloalkyl such as cyclopropyl,cyclobutyl, and cyclopentyl, cycloalkylalkyl such as cyclopropylmethyl.In particular, R¹ is preferably methyl, ethyl or cycloalkyl such ascyclopropyl, cyclobutyl, or cyclopentyl, especially methyl, ethyl andcyclopropyl.

R² is preferably cycloalkyl, aryl, heteroaryl, carbocycle or heterocycle. In particular, R² is preferably cycloalkyl such as cyclopentyl,cyclohexyl, cycloheptyl and norbornyl, aryl which is unsubstituted orsubstituted one or more times by, e.g., halogen, methoxy, nitro, cyano,amino or combinations thereof, heteroaryl such as pyridinyl,pyrimidinyl, thienyl, and furanyl which is unsubstituted or substitutedby, for example, methoxy and/or methylthio, carbocycle such assubstituted or unsubstituted 2-indanyl, or heterocycle such assubstituted or unsubstituted piperidinyl, pyrrolydinyl, andtetrahydrofuranyl.

In addition, preferred PDE4 inhibitors, in accordance with theinvention, are compounds described by subformulas Ia-II, whichcorrespond to formula I, but exhibit the following preferred groups:

-   -   Ia R¹ is alkyl having 1 to 5 C atoms which is unsubstituted or        substituted by hydroxy, cycloalkylalkyl having 4 to 6 carbon        atoms, or is cycloalkyl having 3-5 C atoms; and        -   R² is alkyl having 3 to 8 C atoms, alkyl ether having 3 to 8            carbon atoms, cycloalkyl having 3 to 9 carbon atoms,            cycloalkylalkyl having 4 to 10 carbon atoms, aryl having 6            to 10 carbon atoms, heterocycle having 5 to 10 ring atoms,            heterocycle having 5 to 10 ring atoms, heterocycle-alkyl            having 5 to 10 ring atoms, carbocycle having 5 to 12 carbon            atoms, or heteroaryl, heteroarylalkyl or arylalkyl having 7            to 12 C atoms, wherein the heteroaryl or aryl portion is            unsubstituted or substituted one more times by halogens,            alkyl, CN, alkoxy, nitro, alkoxy, or the combinations            thereof and the alkyl portion is unsubstituted or            substituted by halogen thereof.    -   Ib R¹ is cyclopropyl; and        -   R² is benzyl, phenethyl, or phenpropyl, which in each case            is substituted 1 to 3 times by halogens, C₁₋₄ alkyl, C₁₋₄            alkoxy or combinations thereof.    -   Ic R¹ is cyclopropyl; and        -   R² is alkyl having 3 to 8 C atoms or arylalkyl having 7 to            12 C atoms wherein the aryl portion is substituted one more            time by halogens, alkyl, CN, alkoxy, nitro, or combinations            thereof.    -   Id R¹ is cyclopropyl; and        -   R² is benzyl, 2-methylbenzyl, 3-methylbenzyl,            2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,            2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,            3-methoxybenzyl, 4-cyanobenzyl, 2-triflouromethylbenzyl,            3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl,            3,5-di(trifluoromethyl)benzyl, 2,4-difluorobenzyl,            3,4-difluorobenzyl, 3,5-difluorobenzyl, 2,6-difluorobenzyl,            2,3-difluorobenzyl, 2-chloro-4-fluorobenzyl,            3-chloro-4-chlorobenzyl, 2-chloro-phenethyl,            2-fluoro-phenethyl, 2-methyl-phenethyl, 3-chlorophenethyl,            3-methylphenethyl, 3-methylphenethyl, 3-methoxyphenethyl,            4-chlorophenethyl, 4-methylphenethyl, 4-methoxyphenethyl,            2-methoxy-phenpropyl, 4-chloro-phenpropyl,            4-methoxy-phenpropyl.    -   Ie R¹ is cyclopropyl; and        -   R² is heteroarylalkyl which is unsubstituted or substituted            1 to 3 halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy or combinations            thereof.    -   If R¹ is cyclopropyl; and        -   R² is 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,            2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl or            3-furylmethyl.    -   Ig R¹ is methyl, ethyl, or cyclopropyl; and        -   R² is cycloalkyl.    -   Ih R¹ is methyl, ethyl, or cyclopropyl; and        -   R² is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or            norbornyl.    -   Ii R¹ is methyl, ethyl, or cyclopropyl; and        -   R² is aryl (e.g., phenyl) or substituted aryl (e.g.,            substituted phenyl).    -   Ij R¹ is methyl, ethyl, or cyclopropyl; and        -   R² is carbocycle (e.g., 2-indanyl).    -   Ik R¹ is methyl, ethyl, or cyclopropyl; and        -   R² is heterocycle (e.g., piperidinyl).    -   Il R¹ is methyl, ethyl, or cyclopropyl; and        -   R² is heteroaryl or substituted heteroaryl (e.g.,            substituted or unsubstituted pyrimdinyl, pyridyl, thienyl,            and furanyl.

Preferred aspects include pharmaceutical compositions comprising acompound of this invention and a pharmaceutically acceptable carrierand, optionally, another active agent as discussed below; a method ofinhibiting a PDE4 enzyme, especially an isoenzyme, e.g., as determinedby a conventional assay or one described herein, either in vitro or invivo (in an animal, e.g., in an animal model, or in a mammal or in ahuman); a method of treating neurological syndrome, e.g., loss ofmemory, especially long-term memory, cognitive impairment or decline,memory impairment, etc.; a method of treating a disease state modulatedby PDE4 activity, in a mammal, e.g., a human, e.g., those mentionedherein.

The compounds of the present invention may be prepared conventionally.Some of the processes which can be used are described below. Allstarting materials are known or can be conventionally prepared fromknown starting materials.

2-Substituted hypoxanthines are produced by standard methods in the art,such as by neat reaction between 4-amino-5-imidazolecarboxamide and2,2,2-trifluoroacetamide (E. Richter et al, J. Am. Chem. Soc. 1960, 82,3144-3146; or A. Giner-Sorala, et al, J. Am. Chem. Soc. 1958, 80,5744-5752; or A. Parkin, et al, J. Heterocycl. Chem. 1982, 19, 33-40).6-Halo-2-trifluoromethylpurine may be prepared by methods common in theart (see J.-J. Bourguignon, et al., J. Med. Chem. 1997, 40, 1768-1770;and H. Bader, et al., U.S. Pat. No. 4,405,781, 1983) such as by reactionwith a halogenating reagent such as with SOCl₂, or POCl₃, or PCl₅. Thesereactions can be run neat or with a polar aprotic solvent such asdichloromethane, dichloroethane, or N,N-dimethylformamide. Reaction of a6-halopurine (e.g. 6-chloro-2-trifluoromethylpurine) with either analkyl halide, cycloalkyl halide, cycloalkylalkyl halide, heteroarylhalide or arylalkyl halide in a polar aprotic solvent such asN,N-dimethylforamide, dimethylsulfoxide, or dimethoxyethane in thepresence of a base (e.g. K₂CO₃, Na₂CO₃, NaH) provides a mixture of 9-and 7-substituted 6-halopurines.

The use of a phase transfer catalyst, for example, 18-crown-6 ortetrabutylammonium chloride, with increased reaction temperature, e.g.,60° C. to 150° C., can be used to enhance reaction rates or reactionyields. Alternatively, reaction of a 6-halopurine under Mitsunobuconditions with an alkyl alcohol, cycloalkyl alcohol, arylalkyl alcohol,heteroaryl alcohol, or cycloalkylalkyl alcohol provides a mixture of 9-and 7-substituted 6-halopurines. The 9- and 7-isomers produced by thereactions described above are readily separated by chromatography. Such9-substituted-6-halopurines undergo reaction with amines (e.g. anmmonia,alkylamines, cycloalkylamines, or cycloalkylalkylamines) to provideadenine derivatives of formulas I-III.

Alternatively, 6-halo-2-substituted purines readily undergo reactionwith amines (e.g. ammonia, alkylamines, cycloalkylamines, orcycloalkylalkylamines) in the presence of polar protic solvents (e.g.methanol, ethanol, propanol etc.) to yield 6-N-substituted adenineanalogs. Reaction with either an alkyl halide, cycloalkyl halide,cycloalkylalkyl halide, heteroaryl halide or arylalkyl halide in a polaraprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide, ordimethoxyethane, and in the presence of a base (e.g. K₂CO₃, Na₂CO₃, NaH)provides adenine derivatives of formulas I-III. The use of a phasetransfer catalyst, for example, 18-crown-6 or tetrabutylammoniumchloride, with

increased reaction temperature, e.g., 60° C. to 150° C., can be used toenhance reaction rates or reaction yields. Alternatively, reaction of6-N-substituted adenines under Mitsunobu conditions with an alkylalcohol, cycloalkyl alcohol, arylalkyl alcohol, heteroaryl alcohol, orcycloalkylalkyl alcohol provides 9-substituted 6-N-substituted adeninesof formulas I-III.

6-N-Substituted-9-aryl- and 9-heteroaryl-adenines may be synthesized bymethods common to the art, such as by reaction of a4,6-dichloro-5-aminopyrimidine with an appropriately substituted anilineor heteroarylamine as described by J. L. Kelley et. al., J. Med. Chem.,1997, 40, 3207 to produce 4-arylamino or4-heteroarylamino-6-chloropyrimidines. Cyclization by treating withtriethylorthoformate in the presence of an acid catalyst (e.g.ethylsulfonic acid) provides 6-choro-9-aryl- or 9-heteroaryl-purines,which can be derivatized at the 6-N-position as described above toprovide adenine derivatives of formulas I-III.

Alternatively, 6-N-substituted adenines may undergo a coupling reactionwith arylboronic acids or heteroarylboronic acids in the presence of abase (e.g. triethylamine, pyridine, N—

methylmorpholine), a copper catalyst (e.g., Cu(OAc)₂), and a polaraprotic solvent (e.g. dichloromethane, 1,4-dioxane, THF, DMF, CH₃CN) ina modoified manner as described previously for the N-arylation ofimidazole and pyrazole (see, P. Y. S. Lam et. al. Tetrahedron Lett.1998, 39, 2941-2944) to generate 9-aryl- or 9-heteroaryl-adenines offormulas I-III. Thus, preferably, the use of triethylamine, rather thanpyridine, as a base, and warming to 50-60° C. in CH₃CN, rather thanstirring at room temperature in CH₂Cl₂, provides the novel compounds.

Alternatively, certain halogenated aryl and heteroaryl substrates canundergo aromatic nucleophilic substitution reaction with6-(substituted)amino-2-trifluoromethylpurine in a polar aprotic solvent(e.g., DMF or DMSO) using a base (e.g., cesium carbonate) to providetarget 9-aryl or 9-heteroarylpurines.

Many of these synthetic procedures are described more fully in theexamples below.

One of ordinary skill in the art will recognize that some of thecompounds of Formulas I-III can exist in different geometrical isomericforms. In addition, some of the compounds of the present inventionpossess one or more asymmetric carbon atoms and are thus capable ofexisting in the form of optical isomers, as well as in the form ofracemic or nonracemic mixtures thereof, and in the form of diastereomersand diastereomeric mixtures inter alia. All of these compounds,including cis isomers, trans isomers, diastereomic mixtures, racemates,nonracemic mixtures of enantiomers, and substantially pure and pureenantiomers, are within the scope of the present invention.Substantially pure enantiomers contain no more than 5% w/w of thecorresponding opposite enantiomer, preferably no more than 2%, mostpreferably no more than 1%.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, dibenzoyltartaric,ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomerscan be separated into their individual diastereomers on the basis oftheir physical and/or chemical differences by methods known to thoseskilled in the art, for example, by chromatography or fractionalcrystallization. The optically active bases or acids are then liberatedfrom the separated diastereomeric salts. A different process forseparation of optical isomers involves the use of chiral chromatography(e.g., chiral HPLC columns), with or without conventional derivation,optimally chosen to maximize the separation of the enantiomers. Suitablechiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD andChiracel OJ among many others, all routinely selectable. Enzymaticseparations, with or without derivitization, are also useful. Theoptically active compounds of Formulae I-III can likewise be obtained bychiral syntheses utilizing optically active starting materials.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as pharmaceutically acceptable salts and prodrugsof all the compounds of the present invention. Pharmaceuticallyacceptable salts include those obtained by reacting the main compound,functioning as a base, with an inorganic or organic acid to form a salt,for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid,methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid,succinic acid and citric acid. Pharmaceutically acceptable salts alsoinclude those in which the main compound functions as an acid and isreacted with an appropriate base to form, e.g., sodium, potassium,calcium, mangnesium, ammonium, and choline salts. Those skilled in theart will further recognize that acid addition salts of the claimedcompounds may be prepared by reaction of the compounds with theappropriate inorganic or organic acid via any of a number of knownmethods. Alternatively, alkali and alkaline earth metal salts areprepared by reacting the compounds of the invention with the appropriatebase via a variety of known methods.

The following are further examples of acid salts that can be obtained byreaction with inorganic or organic acids: acetates, adipates, alginates,citrates, aspartates, benzoates, benzenesulfonates, bisulfates,butyrates, camphorates, digluconates, cyclopentanepropionates,dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides,hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates,palmoates, pectinates, persulfates, 3-phenylpropionates, picrates,pivalates, propionates, succinates, tartrates, thiocyanates, tosylates,mesylates and undecanoates.

Preferably, the salts formed are pharmaceutically acceptable foradministration to mammals. However, pharmaceutically unacceptable saltsof the compounds are suitable as intermediates, for example, forisolating the compound as a salt and then converting the salt back tothe free base compound by treatment with an alkaline reagent. The freebase can then, if desired, be converted to a pharmaceutically acceptableacid addition salt.

The compounds of the invention can be administered alone or as an activeingredient of a formulation. Thus, the present invention also includespharmaceutical compositions of compounds of Formula I containing, forexample, one or more pharmaceutically acceptable carriers.

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (current edition).

In view of their high degree of PDE4 inhibition, the compounds of thepresent invention can be administered to anyone requiring or desiringPDE4 inhibition, and/or enhancement of cognition. Administration may beaccomplished according to patient needs, for example, orally, nasally,parenterally (subcutaneously, intraveneously, intramuscularly,intrasternally and by infusion), by inhalation, rectally, vaginally,topically, locally, transdermally, and by ocular administration.

Various solid oral dosage forms can be used for administering compoundsof the invention including such solid forms as tablets, gelcaps,capsules, caplets, granules, lozenges and bulk powders. The compounds ofthe present invention can be administered alone or combined with variouspharmaceutically acceptable carriers, diluents (such as sucrose,mannitol, lactose, starches) and excipients known in the art, includingbut not limited to suspending agents, solubilizers, buffering agents,binders, disintegrants, preservatives, colorants, flavorants, lubricantsand the like. Time release capsules, tablets and gels are alsoadvantageous in administering the compounds of the present invention.

Various liquid oral dosage forms can also be used for administeringcompounds of the invention, including aqueous and non-aqueous solutions,emulsions, suspensions, syrups, and elixirs. Such dosage forms can alsocontain suitable inert diluents known in the art such as water andsuitable excipients known in the art such as preservatives, wettingagents, sweeteners, flavorants, as well as agents for emulsifying and/orsuspending the compounds of the invention. The compounds of the presentinvention may be injected, for example, intravenously, in the form of anisotonic sterile solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the presentinvention can be prepared by mixing the compound with a suitableexcipient such as cocoa butter, salicylates and polyethylene glycols.Formulations for vaginal administration can be in the form of a pessary,tampon, cream, gel, paste, foam, or spray formula containing, inaddition to the active ingredient, such suitable carriers as are knownin the art.

For topical administration the pharmaceutical composition can be in theform of creams, ointments, liniments, lotions, emulsions, suspensions,gels, solutions, pastes, powders, sprays, and drops suitable foradministration to the skin, eye, ear or nose. Topical administration mayalso involve transdermal administration via means such as transdermalpatches.

Aerosol formulations suitable for administering via inhalation also canbe made. For example, for treatment of disorders of the respiratorytract, the compounds according to the invention can be administered byinhalation in the form of a powder (e.g., micronized) or in the form ofatomized solutions or suspensions. The aerosol formulation can be placedinto a pressurized acceptable propellant.

The compounds can be administered as the sole active agent or incombination with other pharmaceutical agents such as other agents usedin the treatment of cognitive impairment and/or in the treatment ofpsychosis, e.g., other PDE4 inhibitors, calcium channel blockers,chloinergic drugs, adenosine receptor modulators, amphakines NMDA-Rmodulators, mGluR modulators, and cholinesterase inhibitors (e.g.,donepezil, rivastigimine, and glanthanamine). In such combinations, eachactive ingredient can be administered either in accordance with theirusual dosage range or a dose below its usual dosage range.

The present invention further includes methods of treatment that involveinhibition of PDE4 enzymes. Thus, the present invention includes methodsof selective inhibition of PDE4 enzymes in animals, e.g., mammals,especially humans, wherein such inhibition has a therapeutic effect,such as where such inhibition may relieve conditions involvingneurological syndromes, such as the loss of memory, especially long-termmemory. Such methods comprise administering to an animal in needthereof, especially a mammal, most especially a human, an inhibitoryamount of a compound, alone or as part of a formulation, as disclosedherein.

The condition of memory impairment is manifested by impairment of theability to learn new information and/or the inability to recallpreviously learned information. Memory impairment is a primary symptomof dementia and can also be a symptom associated with such diseases asAlzheimer's disease, schizophrenia, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovasculardisease, and head trauma as well as age-related cognitive decline.

Dementias are diseases that include memory loss and additionalintellectual impairment separate from memory. The present inventionincludes methods for treating patients suffering from memory impairmentin all forms of dementia. Dementias are classified according to theircause and include: neurodegenerative dementias (e.g., Alzheimer's,Parkinson's disease, Huntington's disease, Pick's disease), vascular(e.g., infarcts, hemorrhage, cardiac disorders), mixed vascular andAlzheimer's, bacterial meningitis, Creutzfeld-Jacob Disease, multiplesclerosis, traumatic (e.g., subdural hematoma or traumatic braininjury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g.,heavy metals, alcohol, some medications), metabolic (e.g., vitamin B12or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric(e.g., depression and schizophrenia), and hydrocephalus.

The present invention includes methods for dealing with memory lossseparate from dementia, including mild cognitive impairment (MCI) andage-related cognitive decline. The present invention includes methods oftreatment for memory impairment as a result of disease. In anotherapplication, the invention includes methods for dealing with memory lossresulting from the use of general anesthetics, chemotherapy, radiationtreatment, post-surgical trauma, and therapeutic intervention.

The compounds may be used to treat psychiatric conditions includingschizophrenia, bipolar or manic depression, major depression, and drugaddiction and morphine dependence. These compounds may enhancewakefulness. PDE4 inhibitors can be used to raise cAMP levels andprevent neurons from undergoing apoptosis. PDE4 inhibitors are alsoknown to be anti-inflammatory. The combination of anti-apoptotic andanti-inflammatory properties make these compounds useful to treatneurodegeneration resulting from any disease or injury, includingstroke, spinal cord injury, neurogenesis, Alzheimer's disease, multiplesclerosis, amylolaterosclerosis (ALS), and multiple systems atrophy(MSA).

Thus, in accordance with a preferred embodiment, the present inventionincludes methods of treating patients suffering from memory impairmentdue to, for example, Alzheimer's disease, schizophrenia, Parkinson'sdisease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease,depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility,multiinfarct dementia and other neurological conditions including acuteneuronal diseases, as well as HIV and cardiovascular diseases,comprising administering an effective amount of a compound according toFormula (I) or (I′) or pharmaceutically acceptable salts thereof.

The compounds of the present invention can also be used in a method oftreating patients suffering from disease states characterized bydecreased NMDA function, such as schizophrenia. The compounds can alsobe used to treat psychosis characterized by elevated levels of PDE 4,for example, various forms of depression, such as manic depression,major depression, and depression associated with psychiatric andneurological disorders.

As mentioned, the compounds of the invention also exhibitanti-inflammatory activity. As a result, the inventive compounds areuseful in the treatment of a variety of allergic and inflammatorydiseases, particularly disease states characterized by decreased cyclicAMP levels and/or elevated phosphodiesterase 4 levels. Thus, inaccordance with a farther embodiment of the invention, there is provideda method of treating allergic and inflammatory disease states,comprising administering an effective amount of a compound according toFormulae (I) or (I′) or a pharmaceutically acceptable salt thereof. Suchdisease states include: asthma, chronic bronchitis, chronic obstructivepulmonary disease (COPD), atopic dermatitis, urticaria, allergicrhinitis, allergic conjunctivitis, vernal conjunctivitis, esoniophilicgranuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis,septic shock, ulcerative colitis, Crohn's disease, reperfusion injury ofthe myocardium and brain, chronic glomerulonephritis, endotoxic shock,adult respiratory distress syndrome, cystic fibrosis, arterialrestenosis, artherosclerosis, keratosis, rheumatoid spondylitis,osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, chronicobstructive airways disease, chronic obstructive pulmonary disease,toxic and allergic contact eczema, atopic eczema, seborrheic eczema,lichen simplex, sunburn, pruritis in the anogenital area, alopeciaareata, hypertrophic scars, discoid lupus erythematosus, systemic lupuserythematosus, follicular and wide-area pyodermias, endogenous andexogenous acne, acne rosacea, Beghet's disease, anaphylactoid purpuranephritis, inflammatory bowel disease, leukemia, multiple sclerosis,gastrointestinal diseases, autoimmune diseases and the like.

PDE4 inhibitors for treating asthma, chronic bronchitis, psoriasis,allergic rhinitis, and other inflammatory diseases, and for inhibitingtumor necrosis factor are known within the art. See, e.g., WO 98/58901,JP11-18957, JP 10-072415, WO 93/25517, WO 94/14742, U.S. Pat. Nos.5,814,651, and 5,935,9778. These references also describe assays fordetermining PDE4 inhibition activity, and methods for synthesizing suchcompounds. The entire disclosures of these documents are herebyincorporated by reference.

PDE4 inhibitors may be used to prevent or ameliorate osteoporosis, as anantibiotic, for treatment of cardiovascular disease by mobilizingcholesterol from atherosclerotic lesions, to treat rheumatoid arthritis(RA), for long-term inhibition of mesenchymal-cell proliferation aftertransplantation, for treatment of urinary obstruction secondary tobenign prostatic hyperplasia, for suppression of chemotaxis andreduction of invasion of colon cancer cells, for treatment of B cellchronic lymphocytic leukemia (B-CLL), for inhibition of uterinecontractions, to attenuate pulmonary vascular ischemia-reperfusioninjury (IRI), for corneal hydration, for inhibition of IL-2R expressionand thereby abolishing HIV-1 DNA nuclear import into memory T cells, foraugmentation of glucose-induced insulin secretion, in both theprevention and treatment of colitis, and to inhibit mast celldegranulation.

The compounds of the present invention can be administered as the soleactive agent or in combination with other pharmaceutical agents such asother agents used in the treatment of cognitive impairment and/or in thetreatment of psychosis, e.g., other PDE4 inhibitors, calcium channelblockers, chloinergic drugs, adenosine receptor modulators, amphakinesNMDA-R modulators, mGluR modulators, and cholinesterase inhibitors(e.g., donepezil, rivastigimine, and glanthanamine). In suchcombinations, each active ingredient can be administered either inaccordance with their usual dosage range or a dose below their usualdosage range.

The dosages of the compounds of the present invention depend upon avariety of factors including the particular syndrome to be treated, theseverity of the symptoms, the route of administration, the frequency ofthe dosage interval, the particular compound utilized, the efficacy,toxicology profile, pharmacokinetic profile of the compound, and thepresence of any deleterious side-effects, among other considerations.

The compounds of the invention are typically administered at dosagelevels and in a mammal customary for PDE4 inhibitors such as those knowncompounds mentioned above. For example, the compounds can beadministered, in single or multiple doses, by oral administration at adosage level of, for example, 0.01-100 mg/kg/day, preferably 0.1-70mg/kg/day, especially 0.5-10 mg/kg/day. Unit dosage forms can contain,for example, 0.1-50 mg of active compound. For intravenousadministration, the compounds can be administered, in single or multipledosages, at a dosage level of, for example, 0.001-50 mg/kg/day,preferably 0.001-10 mg/kg/day, especially 0.01-1 mg/kg/day. Unit dosageforms can contain, for example, 0.1-10 mg of active compound.

In carrying out the procedures of the present invention it is of courseto be understood that reference to particular buffers, media, reagents,cells, culture conditions and the like are not intended to be limiting,but are to be read so as to include all related materials that one ofordinary skill in the art would recognize as being of interest or valuein the particular context in which that discussion is presented. Forexample, it is often possible to substitute one buffer system or culturemedium for another and still achieve similar, if not identical, results.Those of skill in the art will have sufficient knowledge of such systemsand methodologies so as to be able, without undue experimentation, tomake such substitutions as will optimally serve their purposes in usingthe methods and procedures disclosed herein.

The present invention will now be further described by way of thefollowing non-limiting examples. In applying the disclosure of theseexamples, it should be kept clearly in mind that other and differentembodiments of the methods disclosed according to the present inventionwill no doubt suggest themselves to those of skill in the relevant art.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius; and, unless otherwise indicated,all parts and percentages are by weight.

The entire disclosures of all applications, patents and publications,cited above and below, are hereby incorporated by reference.

EXAMPLE 1 1,9-Dihydro-2-trifluoromethyl-6H-purin-6-one (Kelly, J. L.;Linn, J. A.; Selway, J. W. T., J. Med. Chem., 1989, 32, 1757-1763)

A 1 L round-bottom flask (three neck) containing 340 g oftrifluoroacetamide was heated in an oil bath at 110° C. After thetrifluoroacetamide melted, 50 g of 5-aminoimidazole-4-carboxamide-HClwas added. The mixture was warmed to reflux (bath temp 160 to 165° C.)for 4 hours, cooled to room temperature, and the rocky solid wastriturated with 1 L of ether. The ether was decanted off and theremaining solid was warmed until melted and 200 mL of ether wasintroduced by a dropping-funnel through a water-cooled condenser. Themixture was cooled to room temperature and an additional 200 mL of etherwas added with stirring. The solid was removed by filtration, trituratedwith 3×500 mL of ether, washed with 200 mL of H₂O, and filtered toprovide 89 g of crude product. The product was treated with 3 L of MeOHand 9 g of activated carbon, warmed to reflux for 20 minutes, filteredthrough a pad of celite, and concentrated to a volume of 2.5 L. Thematerial was warmed to dissolve all the precipitate that formed and thencooled slowly to room temperature. The crystalline material was isolatedby filtration and dried in vacuo to provide 41 g of the desiredhypoxanthine as a white solid. ¹H NMR (DMSO-d₆) δ 8.34 (s, 1H), 7.18(bs, 2H). MS (ES+), 205.0 (100%, M+H).

EXAMPLE 2 6-Chloro-2-trifluoromethylpurine

A mixture of 15 g (73 mmol) of 2-trifluoromethylhypoxanthine and 300 mLof CHCl₃ was warmed to reflux and treated with a solution of 26.7 mL(366 mmol) SOCl₂ and 28.3 mL (366 mmol) DMF. The reaction was maintainedat reflux for 1.5 h, cooled to room temperature, and poured into 1.2 Lof ice-water. The organic layer was separated and washed with 2×300 mLof H₂O. The pH of the combined aqueous phases was adjusted to 7 withsaturated NaHCO₃ and extracted with 3×1.2 L of ether. The combined etherand chloroform extracts were dried (MgSO₄) and concentrated to drynessto give 7.4 g of crude product. ¹H NMR (DMSO-d₆) δ 14.45 (bs, 1H), 8.95(s, 1H). MS (ES+) 222.96 (100%, M+H).

EXAMPLE 3 6-Chloro-9-(2-fluorobenzyl)-2-trifluoromethylpurine

A mixture of 5 g (22.5 mmol) of 6-chloro-2 trifluoromethylpurine, 4.05 g(29.4 mmol) of anhydrous K₂CO₃, 56 mL of dry DMF, and 3.55 mL (29.4mmol) of 2-fluorobenzyl bromide was stirred at room temperature for 16h. The reaction mixture was poured into 50 mL of ice-water and the pH ofthe solution was adjusted to 5 or 6 with acetic acid. The mixture wasextracted with 3×300 mL of ether and the combined organic fractions werewashed with 3×350 mL of H₂O, 300 mL of brine, dried (Na₂SO₄), andconcentrated in vacuo to provide a yellow oil. Purification bychromatography over silica gel using a gradient elution going from 20%EtOAc in hexanes to 50% EtOAc in hexanes provided 3.5 g (47% yield) ofthe desired 9-isomer (first to elute) and 1.97 g (27% yield) of the7-isomer. ¹H NMR (CDCl₃) δ 8.33 (s, 1H), 7.50-7.47 (m, 1H), 7.40-7.38(m, 1H), 7.20-7.11 (m, 2H), 5.56 (s, 2H).

EXAMPLE 4 6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

A mixture of 100 mg (0.30 mmol) of6-chloro-9-(2-fluorobenzyl)-2-trifluoromethylpurine, 1 mL (14 mmol) ofaminocyclopropane, and 5 mL of EtOH were stirred at room temperature for16 hours. The reaction mixture was concentrated in vacuo and the residuewas dissolved in CH₂Cl₂, washed with 2×5 mL H₂O, 5 mL brine, dried(Na₂SO₄), and concentrated. Chromatography over silica gel using 33%EtOAc in hexanes as eluant provided 102 mg (97% yield) of the desiredproduct. M.P. 118.5-119.0° C.; ¹H NMR (CDCl₃) δ 7.892 (s, 1H), 7.50-7.39(m, 1H), 7.37-7.29 (m, 1H), 7.18-7.05 (m, 2H), 5.95 (bs, 1H), 5.44 (s,2H), 0.94-0.91 (m, 2H), 0.65-0.64 (m, 2H).

To obtain the methansulphonate salt (mesylate salt), 4 ml of 0.1NCH₃SO₃H in EtOAc was added to a solution of 145 mg (0.4 mmol)6-cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine in EtOAc.Then, 1 ml of hexane was added to a warm solution and the resultantmixture was allowed to crystallize (within a refrigerator). The solidwas collected to give 148 mg of the mesylate salt. The salt wasrelatively insoluble in H₂O. M.p. 167.5-169.0 C; m.p. 114-118 C for freebase.

The following compounds were prepared in a similar fashion as describedabove.

-   a. 6-Methylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine-   b. 6-Ethylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine-   c. 6-Amino-9-(2-fluorobenzyl)-2-trifluoromethylpurine-   d.    6-N-Cyclopropylmethylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine-   e.    6-[1-(2-Hydroxy)ethyl]amino-9-(2-fluorobenzyl)-2-trifluoromethylpurine-   f. 6-Cyclopentylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine-   g. 6-Cyclohexylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine-   h. 6-Isopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

EXAMPLE 5 6-Cyclopropylamino-2-trifluoromethylpurine

A mixture of 12 g (54 mmol) of 6-chloro-2-trifluoromethylpurine, 30 g(540 mmol) of cyclopropylamine and 250 mL of ethanol was stirred at roomtemperature for 4.5 days leaving a white solid. The mixture wasconcentrated in vacuo to dryness, 215 mL of H₂O was added and themixture was stirred for 1 hour. The product was collected by filtrationand after drying (vacuum oven, 50° C., 5 hours) 8.1 g of product wasobtained, 62% yield. M.P. 260° C. (dec.); ¹H NMR (CD₃OD) δ 8.18 (s, 1H),3.30 (bs, 1H), 0.904 (m, 2H), 0.67 (m, 2H).

The following compounds are prepared in a similar manner:

-   a. 6-Methylamino-2-trifluuoromethylpurine-   b. 6-Cyclopentylamino-2-trifluoromethylpurine

EXAMPLE 6 6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine

To a nitrogen flushed tube with stir bar was added 25 mg (0.13 mmol) of2-fluorobenzyl bromide, 0.7 mL of anhydrous DMF, 18 mg (0.13 mmol) ofK₂CO₃ and 0.5 mL (0.10 mmol) of 0.2M6-cyclopropylamino-2-trifluoromethyladenine in anhydrous DMF. Thereaction was stirred at room temperature for 18 hours, quenched with 2mL of ice water and the pH was adjusted to between 5 and 6 with aceticacid. The aqueous mixture was extracted with 10 mL of ether and theether fraction was washed with 3 mL of H₂O, 3 mL of brine, dried (MgSO₄)and concentrated to dryness in vacuo. M.P. 118.5-119.0° C.; ¹H NMR(CDCl₃) δ 7.892 (s, 1H), 7.50-7.39 (m, 1H), 7.37-7.29 (m, 1H), 7.18-7.05(m, 2H), 5.95 (bs, 1H), 5.44 (s, 2H), 0.94-0.91 (m, 2H), 0.65-0.64 (m,2H).

The following compounds were prepared in a similar manner.

-   a. 6-Cyclopropylamino-9-(3-methoxybenzyl)-2-trifluoromethylpurine-   b. 6-Cyclopropylamino-9-(3-chlorobenzyl)-2-trifluoromethylpurine-   c. 6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine-   d. 6-Cyclopropylamino-9-(4-cyanobenzyl)-2-trifluoromethylpurine-   e.    6-Cyclopropylamino-9-(4-trifluoromethylbenzyl)-2-trifluoromethylpurine-   f. 6-Cyclopropylamino-9-(3,4-dichlorobenzyl)-2-trifluoromethylpurine-   g. 6-Cyclopropylamino-9-(4-chlorobenzyl)-2-trifluoromethylpurine-   h. 6-Cyclopropylamino-9-(3,4-difluorobenzyl)-2-trifluoromethylpurine-   i. 6-Cyclopropylamino-9-(3-pyridylmethyl)-2-trifluoromethylpurine-   j.    6-Cyclopropylamino-9-[α-(2-chloroacetophenone)]-2-trifluoromethylpurine-   k.    6-Cyclopropylamino-9-[α-(4-methoxyacetophenone)]-2-trifluoromethylpurine-   l. 6-Cyclopropylamino-9-(3,5-difluorobenzyl)-2-trifluoromethylpurine-   m. 6-Cyclopropylamino-9-ethyl-2-trifluoromethylpurine-   n.    6-Cyclopropylamino-9-[α-(4-methylacetophenone)]-2-trifluoromethylpurine-   o.    6-Cyclopropylamino-9-(3-trifluoromethylbenzyl)-2-trifluoromethylpurine-   p.    6-Cyclopropylamino-9-(3,5-bistrifluoromethylbenzyl)]-2-trifluoromethylpurine-   q.    6-Cyclopropylamino-9-(4-methylsulfonylbenzyl)]-2-trifluoromethylpurine-   r. 6-Cyclopropylamino-9-(4-nitrobenzyl)-2-trifluoromethylpurine-   s. 6-Cyclopropylamino-9-(4-tert-butylbenzyl)-2-trifluoromethylpurine-   t. 6-Cyclopropylamino-9-(1-pentan-3-one)-2-trifluoromethylpurine-   u.    6-Cyclopropylamino-9-[α-(2-methoxyacetophenone)]-2-trifluoromethylpurine-   v.    6-Cyclopropylamino-9-[α-(4-cyanoacetophenone)]-2-trifluoromethylpurine-   w.    6-Cyclopropylamino-9-[α-(3-chloroacetophenone)]-2-trifluoromethylpurine-   x.    6-Cyclopropylamino-9-[α-(3-methoxyacetophenone)]-2-trifluoromethylpurine-   y.    6-Cyclopropylamino-9-[α-(4-chloroacetophenone)]-2-trifluoromethylpurine-   z.    6-Cyclopropylamino-9-[α-(3,4-dichloroacetophenone)-2-trifluoromethylpurine-   aa. 6-Cyclopropylamino-9-(4-pyridylmethyl)-2-trifluoromethylpurine-   bb. 6-Cyclopropylamino-9-(2-pyridylmethyl)-2-trifluoromethylpurine-   cc. 6-Cyclopropylamino-9-(4-ethylbenzyl-2-trifluoromethylpurine-   dd.    6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine-   ee.    6-Cyclopropylamino-9-(2,4-dichlorobenzyl)-2-trifluoromethylpurine-   ff.    6-Cyclopropylamino-9-(2,3-dichlorobenzyl)-2-trifluoromethylpurine-   gg.    6-Cyclopropylamino-9-(3,4-ethylenedioxybenzyl)-2-trifluoromethylpurine-   hh.    6-Cyclopropylamino-9-(3,4-methylenedioxybenzyl)-2-trifluoromethylpurine-   ii. 6-Cyclopropylamino-9-(4-isopropylbenzyl)-2-trifluoromethylpurine-   jj. 6-Cyclopropylamino-9-(3-thienylmethyl)-2-trifluoromethylpurine-   kk. 6-Cyclopropylamino-9-(2-thienylmethyl)-2-trifluoromethylpurine-   ll. 6-Cyclopropylamino-9-(2-furylmethyl)-2-trifluoromethylpurine-   mm. 6-Cyclopropylamino-9-(3-furylmethyl)-2-trifluoromethylpurine-   nn.    6-Cyclopropylamino-9-[-(2-(2-chlorophlenyl)ethyl)]-2-trifluoromethylpurine-   oo.    6-Cyclopropylamino-9-[1-(2-(2-fluorophenyl)ethyl)]-2-trifluorometuylpurine-   pp.    6-Cyclopropylamino-9-[1-(2-(2-toluyl)ethyl)]-2-trifluoromethylpurine-   qq.    6-Cyclopropylamino-9-[1-(2-(3-chlorophenyl)ethyl)]-2-trifluoromethylpurine-   rr.    6-Cyclopropylamino-9-[1-(2-(3-toluyl)ethyl)]-2-trifluoromethylpurine-   ss.    6-Cyclopropylamino-9-[1-(2-(3-methoxyphenyl)ethyl)]-2-trifluoromethylpurine-   tt.    6-Cyclopropylamino-9-[1-(2-(4-chlorophenyl)ethyl)]-2-trifluoromethylpurine-   uu.    6-Cyclopropylamino-9-[1-(2-(4-toulyl)ethyl)]-2-trifluoromethylpurine-   vv.    6-Cyclopropylamino-9-[1-(2-(4-methoxyphenyl)ethyl)]-2-trifluoromethylpurine-   ww.    6-Cyclopropylamino-9-[1-(3-(2-methoxyphenyl)propyl)]-2-trifluoromethylpurine-   xx.    6-Cyclopropylamino-9-[1-(3-(4-chlorophenyl)propyl)]-2-trifluoromethylpurine-   yy.    6-Cyclopropylamino-9-[1-(3-(4-methoxyphenyl)propyl)]-2-trifluoromethylpurine-   zz. 6-Cyclopropylamino-9-(3-benzyloxybenzyl)-2-trifluoromethylpurine-   aaa.    6-Cyclopropylamino-9-(2,6-difluorobenzyl)-2-trifluoromethylpurine-   bbb. 6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine-   ccc. 6-Cyclopropylamino-9-(1-propyl)-2-trifluoromethylpurine-   ddd.    6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine-   eee. 6-Cyclopropylamino-9-(4-fluorobenzyl)-2-trifluoromethylpurine-   fff. 6-Cyclopropylamino-9-(2-chlorobenzyl)-2-trifluoromethylpurine-   ggg. 6-Cyclopropylamino-9-(3-methylbenzyl)-2-trifluoromethylpurine-   hhh.    6-Cyclopropylamino-9-(2-chloro-4-fluorobenzyl)-2-trifluoromethylpurine-   iii.    6-Cyclopropylamino-9-[1-(2-methoxyethyl)]-2-trifluoromethylpurine-   jjj. 6-Cyclopropylamino-9-(2-butyl)-2-trifluoromethylpurine-   kkk. 6-Cyclopropylamino-9-(1-butyl)-2-trifluoromethylpurine-   lll. 6-Cyclopropylamino-9-(2-methylbenzyl)-2-trifluoromethylpurine-   mmm. 6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine-   nnn.    6-Cyclopropylamino-9-(2,4-difluorobenzyl)-2-trifluoromethylpurine-   ooo. 6-Cyclopropylamino-9-(2-nitrobenzyl)-2-trifluoromethylpurine-   ppp. 6-Cyclopropylamino-9-benzyl-2-trifluoromethylpurine-   qqq. 6-Cyclopropylamino-9-(2-propyl)-2-trifluoromethylpurine-   rrr.    6-Cyclopropylamino-9-(2-trifluromethylbenzyl)-2-trifluoromethylpurine-   sss. 6-Cyclopropylamino-9-(3-fluorobenzyl)-2-trifluoromethylpurine-   ttt. 6-Cyclopropylamino-9-(4-phenylbenzyl)-2-trifluoromethylpurine-   uuu. 6-Cyclopropylamino-9-(2-phenylbenzyl)-2-trifluoromethylpurine-   vvv. 6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine-   www. 6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine

The following compounds can be prepared in a manner similar to thatdescribed in Example 6 using cesium carbonate rather than potassiumcarbonate:

-   a.    6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpurine-   b. 6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine-   c. 6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine-   d. 6-Cyclopropylamino-9-(2-pyrimidyl)-2-trifluoromethylpurine-   e.    6-Cyclopropylamino-9-(4-(2-diethylamino)pyrimidyl)-2-trifluoromethylpurine-   f.    6-Cyclopropylamino-9-(4-(2-chloro)pyrimidyl)-2-trifluoromethylpurine-   g.    6-Cyclopropylamino-9-(4-(2-methylthio)pyrimidyl)-2-trifluoromethylpurine

The following compounds can be prepared in a manner similar to thatabove using 6-N-methylamino-2-trifluoromethylpurine as a startingmaterial:

-   a. 6-N-methylamino-9-cyclopentyl-2-trifluoromethylpurine-   b. 6-N-methylamino-9-cycloheptyl-2-trifluoromethylpurine

The following compound can be prepared in a manner similar to thatdescribed above using 6-N-cyclopentylamino-2-trifluoromethylpurine as astarting material:

-   a. 6-N-cyclopentylamino-9-methyl-2-trifluoromethylpurine.

EXAMPLE 7 6-Cyclopropylamino-9-(3-aminophenyl)-2-trifluoromethylpurine

A mixture of6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine (0.1 mmol),palladium on active carbon (0.001 mol) methanol (50 ml) and acetic acid(3 ml) was shaken under 30 psi hydrogen. After 5 hours, the reactionmixture was filtered through celite and the filtrate was concentrated invacuo. The resultant residue was dissolved in 30 ml of ethyl acetate,washed with 30 mL of aqueous 5% sodium bicarbonate, concentrated andpurified by chromatography over SiO₂ to give the amino product inquantitative yield. ¹H NMR (300 MHz, CDCl₃) □ 8.10 (s, 1H), 7.27 (t,J=8.1 Hz, 1H), 7.05 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.70 (d, J=8.1 Hz,1H), 6.35(b, 1H), 3.18 (b, 1H), 0.91 (m, 2H), 0.69 (m, 2H).

The following compounds can be made in a similar manner:

6-Cyclopropylamino-9-(3-aminobenzyl)-2-trifluoromethylpurine

EXAMPLE 8 6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine(Pragnacharyulu, P. V. P.; Varkhedkar, V.; Curtis, M. A.; Chang, I. F.;Abushanab, E., J. Med. Chem., 2000, 43, 4694-4700).

To a solution of 20 mg (0.08 mmol)6-cyclopropylamino-2-trifluoromethylpurine, 42 mg (0.16 mmol) of PPh₃,and 18 mg (0.21 mmol) cyclopentanol in THF under N₂ atmosphere withmagnetic stirring, was added 48 mg (0.23 mmol) DIAD. The resultingmixture was stirred at room temperature for 16 hours, concentrated,taken up in 10 mL H₂O and extracted with 2×15 mL of ether. The organiclayer was combined and dried over (MgSO₄), concentrated in vacuo, andpurified by chromatography over silica gel using 10% MeOH in CH₂Cl₂ togive the desired product. ¹H NMR (CDCl₃) 7.92 (s, 1H), 6.01 (bs, 1H),4.98 (p, 1H), 3.18 (bs, 1H), 2.36-2.25 (m, 2H), 2.03-1.79 (m, 6H), 0.86(dd, 2H), 0.65 (dd, 2H).

The following compounds were prepared in a similar manner:

-   a. 6-Cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine-   b. 6-Cyclopropylamino-9-cyclopentylethyl-2-trifluoromethylpurine-   c. 6-Cyclopropylamino-9-cyclopentylpropyl-2-trifluoromethylpurine-   d.    6-Cyclopropylamino-9-(3-(1-ethyl-pyrrolidinyl)-2-trifluoromethylpurine-   e.    6-Cyclopropylamino-9-(3-(1-ethyl-piperidinyl)-2-trifluoromethylpurine-   f.    6-Cyclopropylamino-9-(2-(1-ethyl-piperidinyl)-2-trifluoromethylpurine-   g.    6-Cyclopropylamino-9-(piperidin-1-ylethyl)-2-trifluoromethylpurine-   h.    6-Cyclopropylamino-9-(2-(1-methyl-piperidinyl)-2-trifluoromethylpurine-   i.    6-Cyclopropylamino-9-(5-oxo-(S)-pyrrolidin-3-yl)-2-trifluoromethylpurine-   j.    6-Cyclopropylamino-9-(5-oxo-(R)-pyrrolidin-3-yl)-2-trifluoromethylpurine

EXAMPLE 96-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine

A mixture of 6-cyclopropylamino-2-trifluoromethyladenine (46 mg, 0.2mmol), 3,4-dimethoxyphenyl boronic acid (44 mg, 0.24 mmol), copper(II)acetate (36 mg, 0.2 mmol), triethylamine (1.0 mmol, 101 mg), anhydrousacetonitrile (4 ml) and molecular seives (˜10 pellets) was stirred at50-55° C. for 18 hours. Ethyl acetate (20 ml) was added and the solidwas removed by filtration. The filtrate was washed with 20 ml of 5%sodium bicarbonate aqueous solution. Evaporation and chromatography overSiO₂ using hexane/ethylacetate/methanol (50:50:1) as elunt gave 7.9 mgof the title compound (yield 10%). ¹H NMR (300 MHz, CDCl₃) δ 8.10 (s,1H), 7.39 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H),6.35(b, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.18 (b, 1H), 0.91 (m, 2H),0.69 (m, 2H)

The following compounds were prepared in a similar manner:

-   a.    6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine-   b. 6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine-   c. 6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine-   d. 6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine-   e. 6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine-   f. 6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine-   g. 6-Cyclopropylamino-9-(2,5-dimethoxphenyl)-2-trifluoromethylpurine-   h.    6-Cyclopropylamino-9-(2,4-dimethoxypyrimidyl)-2-trifluoromethylpurine-   i.    6-Cyclopropylamino-9-(2-methoxy-5-pyridyl)-2-trifluoromethylpurine-   j. 6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine-   k. 6-Cyclopropylamino-9-(3-pyridyl)-2-trifluoromethylpurine-   l.    6-Cyclopropylamino-9-(1-tert-butoxycarbonyl-pyrrol-2-yl)-2-trifluoromethylpurine-   m.    6-Cyclopropylamino-9-(4-dimethylaminophenyl)-2-trifluoromethylpurine-   n.    6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine-   o. 6-Methylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine-   p. 6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine-   q. 6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine-   r. 6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine-   s. 6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine-   t. 6-Cyclopropylamino-9-(3-furanyl)-2-trifluoromethylpurine-   u. 6-Cyclopropylamino-9-(4-ethoxyphenyl)-2-trifluoromethylpurine-   v. 6-Cyclopropylamino-9-(2-ethoxyphenyl)-2-trifluoromethylpurine-   w.    6-Cyclopropylamino-9-(3,4-methylenedioxyphenyl)-2-trifluoromethylpurine-   x. 6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine-   y. 6Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine-   z.    6-Cyclopropylamino-9-(3,5-dimethoxyphenyl)-2-trifluoromethylpurine-   aa.    6-Cyclopropylamino-9-(2-methoxy-5-chlorophenyl)-2-trifluoromethylpurine-   bb. 6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine-   cc. 6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine-   dd. 6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine-   ee. 6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine-   ff. 6-Cyclopropylamino-9-(4-toluyl)-2-trifluoromethylpurine-   gg.    6-Cyclopropylamino-9-(4-trifluoromethylphenyl)-2-trifluoromethylpurine-   hh. 6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine-   ii.    6-Cyclopropylamino-9-(3-trifluoromethylphenyl)-2-trifluoromethylpurine

EXAMPLE 10 In Vitro Measurement of Type 4 Phosphodiesterase InhibitionActivity

Human PDE4 was obtained from baculovirus-infected Sf9 cells thatexpressed the recombinant enzyme. The cDNA encoding hPDE-4D6 wassubcloned into a baculovirus vector. Insect cells (Sf9) were infectedwith the baculovirus and cells were cultured until protein wasexpressed. The baculovirus-infected cells were lysed and the lysate wasused as source of hPDE-4D6 enzyme. The enzyme was partially purifiedusing a DEAE ion exchange chromatography. This procedure can be repeatedusing cDNA encoding other PDE-4 enzymes.

Assay:

Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP)to 5′-adenosine monophosphate (5′-AMP). Nucleotidase converts 5′-AMP toadenosine. Therefore the combined activity of PDE4 and nucleotidaseconverts cAMP to adenosine. Adenosine is readily separated from cAMP byneutral alumina columns. Phosphodiesterase inhibitors block theconversion of cAMP to adenosine in this assay; consequently, PDE4inhibitors cause a decrease in adenosine.

Cell lysates (40 ul) expressing hPDE-4D6 were combined with 50 ul ofassay mix and 10 ul of inhibitors and incubated for 12 min at roomtemperature. Final concentrations of assay components were: 0.4 ugenzyme, 10 mM Tris-HCl (pH 7.5), 10 mM MgCl₂, 3 uM cAMP, 0.002 U5′-nucleotidase, and 3×10⁴ cpm of [3H]cAMP. The reaction was stopped byadding 100 μl of boiling 5 mN HCl. An aliquot of 75 μl of reactionmixture was transferred from each well to alumina columns (Multiplate;Millipore). Labeled adenosine was eluted into an OptiPlate by spinningat 2000 rpm for 2 min; 150 μl per well of scintillation fluid was addedto the OptiPlate. The plate was sealed, shaken for about 30 min, and cpmof [³H]adenosine was determined using a Wallac Trilux®.

All test compounds are dissolved in 100% DMSO and diluted into the assaysuch that the final concentration of DMSO is 0.1%. DMSO does not affectenzyme activity at this concentration.

A decrease in adenosine concentration is indicative of inhibition of PDEactivity. pIC₅₀ values were determined by screening 6 to 12concentrations of compound ranging from 0.1 nM to 10,000 nM and thenplotting drug concentration versus ³H-adenosine concentration. Nonlinearregression software (Assay Explorer®) was used to estimate pIC₅₀ values.

EXAMPLE 11 Passive Avoidance in Rats, an in vivo Test for Learning andMemory

The test was performed as previously described (Zhang, H.-T., Crissman,A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M.,Neuropsychopharmacology, 2000, 23, 198-204.). The apparatus (ModelE10-16SC, Coulbourn Instruments, Allentown, Pa.) consisted of atwo-compartment chamber with an illuminated compartment connected to adarkened compartment by a guillotine door. The floor of the darkenedcompartment consisted of stainless steel rods through which an electricfoot-shock could be delivered from a constant current source. Allexperimental groups were first habituated to the apparatus the daybefore the start of the experiment. During the training, the rat (MaleSpraque-Dawley (Harlan) weighing 250 to 350 g) was placed in theilluminated compartment facing away from the closed guillotine door for1 minute before the door was raised. The latency for entering thedarkened compartment was recorded. After the rat entered the darkenedcompartment, the door was closed and a 0.5 mA electric shock wasadministered for 3 seconds. Twenty-four hours later, the rat wasadministered 0.1 mg/kg MK-801 or saline, 30 minutes prior to theinjection of saline or test compound (dosed from 0.1 to 2.5 mg/kg,i.p.), which was 30 minutes before the retention test started. The ratwas again placed in the illuminated compartment with the guillotine dooropen. The latency for entering the darkened compartment was recorded forup to 180 seconds, at which time the trial was terminated.

All data were analyzed by analyses of variance (ANOVA); individualcomparisons were made using Kewman-Keuls tests. Naive rats required lessthan 30 seconds, on average, to cross from the illuminated compartmentto the darkened compartment. However, 24 hours after the electric shockexposure, most rats pretreated with vehicle did not re-enter thedarkened compartment; the average latency was increased up to 175seconds (p<0.001). Pretreatment with MK-801 (0.1 mg/kg) markedly reducedthis latency when compared to the vehicle (p<0.001). This amnesic effectof MK-801 is reversed in a statistically significant manner by actualtest compounds in a dose-dependent fashion.

EXAMPLE 12 Radial Arm Maze Task in Rats, an in vivo Test for Learningand Memory

The test was performed as previously described (Zhang, H.-T., Crissman,A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M.,Neuropsychopharmacology, 2000, 23, 198-204.). Five days after initialhousing, rats (male Spraque-Dawley (Harlan) weighing 250 to 350 g) wereplaced in the eight-arm radial maze (each arm was 60×10×12 cm high; themaze was elevated 70 cm above the floor) for acclimation for two days.Rats were then placed individually in the center of the maze for 5minutes with food pellets placed close to the food wells, and then, thenext day, in the wells at the end of the arms; 2 sessions a day wereconducted. Next, four randomly selected arms were then baited with onepellet of food each. The rat was restricted to the center platform (26cm in diameter) for 15 seconds and then allowed to move freelythroughout the maze until it collected all pellets of food or 10 minutespassed, whichever came first. Four parameters were recorded: 1) workingmemory errors, i.e., entries into baited arms that had already beenvisited during the same trial; 2) reference memory errors, i.e., entriesinto unbaited arms; 3) total arm entries; and 4) the test duration(seconds), i.e., the time spent in the collection of all the pellets inthe maze. If the working memory error was zero and the average referencememory error was less than one in five successive trials, the rats beganthe drug tests. MK-801 or saline was injected 15 minutes prior tovehicle or test agent, which was given 45 minutes before the test.Experiments were performed in a lighted room, which contained severalextra-maze visual cues.

All data were analyzed by analyses of variance (ANOVA); individualcomparisons were made using Kewman-Keuls tests. Compared to control,MK-801 (0.1 mg/kg, i.p.) increased the frequencies of both working andreference memory errors (p<0.01). This amnesic effect of MK-801 onworking memory is reversed in a statistically significant manner by theadministration of actual test compounds in a dose-dependent fashion.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

While the invention has been illustrated with respect to the productionand of particular compounds, it is apparent that variations andmodifications of the invention can be made without departing from thespirit or scope of the invention.

1. A compound of Formula I:

wherein, R¹ is alkyl having 1 to 5 carbon atoms, which is substitutedone or more times by halogen, hydroxy, or combinations thereof, andwherein a —CH₂— group can be optionally replaced by —O—, —S—, or —NH—,cycloalkyl having 3 to 6 carbon atoms, or cycloalkylalkyl having 4 to 7carbon atoms; and R² is alkyl having 1 to 12 carbon atoms, which isunsubstituted or substituted one or more times by halogen, hydroxy,cyano or combinations thereof, wherein one or more —CH₂— groups is eachindependently optionally replaced by —O—, —S—, or —NH—, and whereinoptionally one or more —CH₂CH₂— groups is replaced in each case by—CH═CH— or —C≡C—, alkoxyalkyl having 3 to 12 carbon atoms, cycloalkylhaving 3 to 12 carbon atoms, which is unsubstituted or substituted oneor more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄alkoxy, cyano or combinations thereof, cycloalkylalkyl having to 12carbon atoms which is unsubstituted or substituted one or more times byC₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, halogen, orcombinations thereof, aryl having 6 to 14 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, —C(O)—NHOH, —C(O)—NH₂, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, arylalkyl having 7 to 16 carbon atoms, which issubstituted one or more times by halogen, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH,—C(O)—NH₂, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or substituted one or moretimes by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl,—C(O)—NHOH, —C(O)—NH₂, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, or combinations thereof, heteroarylalkyl whereinthe heteroaryl portion has 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, theheteroaryl portion is unsubstituted or is substituted one or more timesby halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl,—C(O)—NHOH, —C(O)—NH₂, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, or combinations thereof, heterocycle having 5 to 10ring atoms in which at least 1 ring atom is a heteroatom, which isunsubstituted or is substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof;heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonaromatic and isunsubstituted or is substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof, orcarbocycle which is nonaromatic, monocyclic or bicyclic, group having 5to 14 carbon atoms, which is unsubstituted or is substituted one or moretimes by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH,—C(O)—NH₂, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof; and pharmaceutically acceptable salts thereof, with the provisothat when R¹ is cyclopropyl, then R² is not cyclopropylmethyl, orcyclopropylethyl.
 2. A compound according to claim 1, wherein R¹ issubstituted alkyl.
 3. A compound according to claim 1, wherein R¹ iscycloalkyl.
 4. A compound according to claim 1, wherein R¹ iscycloalkylalkyl.
 5. A compound according to claim 1, wherein R² issubstituted or unsubstituted alkyl.
 6. A compound according to claim 1,wherein R² is alkoxyalkyl.
 7. A compound according to claim 1, whereinR² is substituted or unsubstituted cycloalkyl.
 8. A compound accordingto claim 1, wherein R² is substituted or unsubstituted aryl.
 9. Acompound according to claim 1, wherein R² is substituted orunsubstituted arylalkyl.
 10. A compound according to claim 1, wherein R²is substituted or unsubstituted heteroaryl.
 11. A compound according toclaim 1, wherein R² is substituted or unsubstituted heteroarylalkyl. 12.A compound according to claim 1, wherein R² is substituted orunsubstituted heterocycle.
 13. A compound according to claim 1, whereinR² is substituted or unsubstituted heterocycle-alkyl.
 14. A compoundaccording to claim 1, wherein R² is substituted or unsubstitutedcarbocycle.
 15. A compound according to claim 1, wherein R¹ iscycloalkyl or cycloalkylalkyl.
 16. A compound according to claim 5,wherein R¹ is cycloalkyl or cycloalkylalkyl.
 17. A compound according toclaim 6, wherein R¹ is cycloalkyl or cycloalkylalkyl.
 18. A compoundaccording to claim 7, wherein R¹ is cycloalkyl or cycloalkylalkyl.
 19. Acompound according to claim 8, wherein R¹ is cycloalkyl orcycloalkylalkyl.
 20. A compound according to claim 9, wherein R¹ iscycloalkyl or cycloalkylalkyl.
 21. A compound according to claim 10,wherein R¹ is cycloalkyl or cycloalkylalkyl.
 22. A compound according toclaim 11, wherein R¹ is cycloalkyl or cycloalkylalkyl.
 23. A compoundaccording to claim 12, wherein R¹ is cycloalkyl or cycloalkylalkyl. 24.A compound according to claim 13, wherein R¹ is cycloalkyl orcycloalkylalkyl.
 25. A compound according to claim 14, wherein R¹ iscycloalkyl or cycloalkylalkyl.
 26. A compound according to claim 1,wherein R¹ is cyclopropyl, cyclopentyl, or cyclopropylmethyl.
 27. Acompound according to claim 1, wherein R¹ is cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.
 28. A compound according to claim 1, whereinR¹ is cyclopropyl.
 29. A compound according to claim 1, wherein R² isalkyl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, oralkoxyalkyl.
 30. A compound according to claim 1, wherein R² is ethyl,isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, orarylalkyl which is unsubstituted or substituted one or more times by F,Cl, CN, CF₃, CH₃, C₂H₅, isopropyl, OCH₃, methylenedioxy, ethylenedioxyor combinations thereof.
 31. A compound according to claim 1, wherein R²is substituted or unsubstituted benzyl, phenethyl or phenpropyl.
 32. Acompound of formula II

wherein R^(1′) is methyl, ethyl, or cyclopropyl; and R^(2′) iscycloalkyl having 3 to 12 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, C₁₋₄ alkoxy, cyano or combinations thereof, aryl having 6 to 14carbon atoms, which is unsubstituted or substituted one or more times byhalogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,C₁₋₄ alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,C₁₋₄-hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH, —C(O)—NH₂, C₂₋₄-acyl,C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, phenoxy, or combinations thereof, heteroaryl having5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, whichis unsubstituted or substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, —C(O)—NHOH, —C(O)—NH₂,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, orcombinations thereof, heterocycle having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom, which is unsubstituted or issubstituted one or more times by halogen, aryl, C₁₋₄ alkyl, halogenatedC₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino,carboxy, alkoxycarbonyl, or combinations thereof, or carbocycle which isnonaromatic, monocyclic or bicyclic, group having 5 to 14 carbon atoms,which is unsubstituted or is substituted one or more times by halogen,C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenatedC₁₋₄ alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy,carboxy, cyano, —C(O)—NHOH, —C(O)—NH₂, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof; and pharmaceutically acceptable salts thereof. 33.A compound of Formula III:

wherein R^(1″) is methyl, ethyl, or cyclopropyl; and R^(2″) is phenyl,phenyl which is substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-acyl,C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, phenoxy, or combinations thereof, or heteroarylhaving 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom,substituted heteroaryl having 5 to 10 ring atoms, in which at least 1ring atom is a heteroatom, which is unsubstituted or substituted one ormore times by halogen, aryl, C₁₋₄-alkyl, C₁₋₄-alkoxy, cyano,trifluoromethyl, nitro, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino orcombinations thereof, or when R¹ is methyl or cyclopropyl R² can also becycloalkyl having 3 to 12 carbon atoms; and pharmaceutically acceptablesalts thereof.
 34. A compound selected from:6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-fluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,6-difluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-propyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-methylenedioxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-thiophenemethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine6-Methylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine6-Methylamino-9-cycloheptyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-norboranane)-2-trifluoromethylpurine6-Cyclopropylamino-9-(1-indanyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-cyclopentyloxy-4-methoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,4-dimethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(6-methoxy-3-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-pyridyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-dimethylaminophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-aminophenyl)-2-trifluoromethylpurine6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine6-Methylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-furanyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-ethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-ethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-methylenedioxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine; andpharmaceutically acceptable salts thereof.
 35. A compound according toclaim 34, wherein said compound is selected from:6-Cyclopropylamino-9-(2,3-difluorobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine6-Methylamino-9-cyclopentyl-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine6-Methylamino-9-cycloheptyl-2-trifluoromethylpurine6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-norboranane)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2,6-dichloro-4-pyridylmethyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine6-Methylamino-9-(2,4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine; andpharmaceutically acceptable salts thereof.
 36. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically acceptable carrier.
 37. A composition according toclaim 36, wherein said composition contains 0.1-50 mg of said compound.38. A process for preparing compounds of the formula IV

wherein R¹ is H, alkyl having 1 to 5 carbon atoms, which is unsustitutedor substituted one or more times by halogen, hydroxy, or combinationsthereof, and wherein a —CH₂— group can be optionally replaced by —O—,—S—, or —NH—, cycloalkyl having 3 to 6 carbon atoms, or cycloalkylalkylhaving 4 to 7 carbon atoms; and R² is aryl having 6 to 14 carbon atoms,which is unsubstituted or substituted one or more times by halogen, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, —C(O)—NHOH, —C(O)—NH₂, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, heteroaryl having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom, which is unsubstituted or substitutedone or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, —C(O)—NHOH, —C(O)—NH₂, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof, saidprocess comprising: reacting 6-N-R¹-2-CF-substituted adenine with anarylboronic acid or heteroarylboronic acid in the presence oftrialkylamine wherein the alkyl portions each have 1 to 5 carbon atomsas a base, a copper catalyst, and a polar aprotic solvent, at atemperature of at least 50° C.
 39. A compound according to claim 1,wherein R² is cycloalkylalkyl.
 40. A compound according to claim 39,wherein R¹ is cycloalkyl or cycloalkylalkyl.
 41. A compound according toclaim 1, wherein said compound is6-cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine, or apharmaceutically acceptable salt thereof.
 42. A compound according toclaim 1, wherein said compound is6-cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine, or apharmaceutically acceptable salt thereof.
 43. A compound according toclaim 1, wherein R¹ is cycloalkyl and R² is phenyl or heteroaryl, ineach case substituted or unsubstituted.
 44. A compound according toclaim 1, wherein R² is alkyl having 1 to 12 carbon atoms, which isunsubstituted or substituted one or more times by halogen, hydroxy,cyano or combinations thereof, wherein one or more —CH₂— groups is eachindependently optionally replaced by —O—, —S—, or —NH—, and whereinoptionally one or more —CH₂CH₂— groups is replaced in each case by—CH═CH— or —C≡C—, alkoxyalkyl having 3 to 12 carbon atoms, cycloalkylhaving 3 to 12 carbon atoms, which is unsubstituted or substituted oneor more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄alkoxy, cyano or combinations thereof, cycloalkylalkyl having 4 to 12carbon atoms, which is unsubstituted or substituted one or more times byC₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, halogen, orcombinations thereof, aryl having 6 to 14 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, C₂₋₄-alkanoyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof, arylalkyl having 7 to 16 carbon atoms, which is unsubstitutedor substituted one or more times by halogen, C₁₋₄ alkyl, halogenatedC₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, C₂₋₄— alkanoyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or substituted one or moretimes by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, orcombinations thereof, heteroarylalkyl wherein the heteroaryl portion has5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and thealkyl portion has 1 to 3 carbon atoms, the heteroaryl portion isunsubstituted or is substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,heterocycle having 5 to 10 ring atoms in which at least 1 ring atom is aheteroatom, which is unsubstituted or is substituted one or more timesby halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, or combinations thereof; heterocycle-alkyl wherein theheterocycle portion has 5 to 10 ring atoms in which at least 1 ring atomis a heteroatom and the alkyl portion has 1 to 3 carbon atoms, theheterocycle portion is nonaromatic and is unsubstituted or issubstituted one or more times by halogen, aryl, C₁₋₄ alkyl, halogenatedC₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino,carboxy, alkoxycarbonyl, or combinations thereof, or carbocycle which isa nonaromatic, monocyclic or bicyclic, group having 5 to 14 carbonatoms, which is unsubstituted or is substituted one or more times byhalogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,C₁₋₄ alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-alkanoyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof.
 45. A compound according to claim 32, whereinR^(2′) is cycloalkyl having 3 to 12 carbon atoms, which is unsubstitutedor substituted one or more times by halogen, C₁₋₄ alkyl, halogenatedC₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or combinations thereof, aryl having 6 to14 carbon atoms, which is unsubstituted or substituted one or more timesby halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy,halogenated C₁₋₄ alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,C₁₋₄ alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-alkanoyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, heteroaryl having 5 to 10 ring atoms in which atleast 1 ring atom is a heteroatom, which is unsubstituted or substitutedone or more times by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl,hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl,nitro, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy,alkoxycarbonyl, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, or combinations thereof, heterocycle having 5 to 10ring atoms in which at least 1 ring atom is a heteroatom, which isunsubstituted or is substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof, orcarbocycle which is a nonaromatic, monocyclic or bicyclic, group having5 to 14 carbon atoms, which is unsubstituted or is substituted one ormore times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-alkanoyl,C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, phenoxy, or combinations thereof.
 46. A compoundaccording to claim 33, wherein R^(2″) isphenyl, phenyl which issubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, nitro, methylenedioxy, ethylenedioxy,amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-alkanoyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, or heteroaryl having 5 to 10 ring atoms in whichat least 1 ring atom is a heteroatom, substituted heteroaryl having 5 to10 ring atoms, in which at least 1 ring atom is a heteroatom, which isunsubstituted or substituted one or more times by halogen, aryl,C₁₋₄-alkyl, C₁₋₄-alkoxy, cyano, trifluoromethyl, nitro, amino,C₁₋₄-alkylamino, di-C₁₋₄-alkylamino or combinations thereof.
 47. Acompound according to claim 1, wherein R¹ is cyclopropyl; and R² isalkyl having 1 to 12 carbon atoms, which is unsubstituted or substitutedone or more times by halogen, hydroxy, cyano or combinations thereof,wherein one or more —CH₂— groups is each independently optionallyreplaced by —O—, —S—, or —NH—, and wherein optionally one or more—CH₂CH₂— groups is replaced in each case by —CH═CH— or —C≡C—, cycloalkylhaving 3 to 12 carbon atoms, which is unsubstituted or substituted oneor more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄alkoxy, cyano or combinations thereof, cycloalkylalkyl having 4 to 12carbon atoms, which is unsubstituted or substituted one or more times byC₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, halogen, orcombinations thereof, aryl having 6 to 14 carbon atoms, which isunsubstituted or substituted one or more times by halogen, halogenatedC₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, or combinations thereof, arylalkyl having 7 to 16carbon atoms, which is unsubstituted or substituted one or more times byhalogen, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, nitro, methylenedioxy, ethylenedioxy, or combinations thereof,heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is aheteroatom, which is unsubstituted or substituted one or more times byhalogen, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, or combinations thereof,heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms inwhich at least 1 ring atom is a heteroatom and the alkyl portion has 1to 3 carbon atoms, the heteroaryl portion is unsubstituted or issubstituted one or more times by halogen, aryl, C₁₋₄ alkyl, halogenatedC₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano,trifluoromethyl, nitro, amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino,carboxy, alkoxycarbonyl, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, or combinations thereof, heterocycle having 5 to 10ring atoms in which at least 1 ring atom is a heteroatom, which isunsubstituted or is substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof;heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonaromatic and isunsubstituted or is substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof, orcarbocycle which is a nonaromatic, monocyclic or bicyclic, group having5 to 14 carbon atoms, which is unsubstituted or is substituted one ormore times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-alkanoyl,C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, phenoxy, or combinations thereof.
 48. A compoundaccording to claim 33, wherein R^(2″) is phenyl, or phenyl which issubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, nitro, methylenedioxy, ethylenedioxy,amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl,C₁₋₄-hydroxyalkoxy, carboxy, cyano, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof.
 49. A compound according to claim 1, wherein whenR¹ is cyclopropyl, R² is not cycloalkylalkyl.
 50. A compound accordingto claim 1, wherein R² is alkyl having 1 to 12 carbon atoms, which isunsubstituted or substituted one or more times by halogen, hydroxy,cyano or combinations thereof, wherein one or more —CH₂— groups is eachindependently optionally replaced by —O—, —S—, or —NH—, and whereinoptionally one or more —CH₂CH₂— groups is replaced in each case by—CH═CH— or —C≡C—, alkoxyalkyl having 3 to 12 carbon atoms, cycloalkylhaving 3 to 12 carbon atoms, which is unsubstituted or substituted oneor more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄alkoxy, cyano or combinations thereof, cycloalkylalkyl having 4 to 12carbon atoms, which is unsubstituted or substituted one or more times byC₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, halogen, orcombinations thereof, aryl having 6 to 14 carbon atoms, which isunsubstituted or substituted one or more times by halogen, C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, —C(O)—NHOH, —C(O)—NH₂, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, arylalkyl having 7 to 16 carbon atoms, which issubstituted one or more times by halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH,—C(O)—NH₂, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or substituted one or moretimes by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl,—C(O)—NHOH, —C(O)—NH₂, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, or combinations thereof, heteroarylalkyl whereinthe heteroaryl portion has 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, andthe heteroaryl portion is unsubstituted or substituted one or more timesby halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl,—C(O)—NHOH, —C(O)—NH₂, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, or combinations thereof, heterocycle having 5 to 10ring atoms in which at least 1 ring atom is a heteroatom, which isunsubstituted or is substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof,heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonaromatic and isunsubstituted or is substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof, orcarbocycle which is nonaromatic, monocyclic or bicyclic, group having 5to 14 carbon atoms, which is unsubstituted or is substituted one or moretimes by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH,—C(O)—NH₂, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof.
 51. A compound according to claim 49, wherein R² is alkylhaving 1 to 12 carbon atoms, which is unsubstituted or substituted oneor more times by halogen, hydroxy, cyano or combinations thereof,wherein one or more —CH₂— groups is each independently optionallyreplaced by —O—, —S—, or —NH—, and wherein optionally one or more—CH₂CH₂— groups is replaced in each case by —CH═CH— or —C≡C—,alkoxyalkyl having 3 to 12 carbon atoms, cycloalkyl having 3 to 12carbon atoms, which is unsubstituted or substituted one or more times byhalogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano orcombinations thereof, cycloalkylalkyl having 4 to 12 carbon atoms, whichis unsubstituted or substituted one or more times by C₁₋₄ alkyl,halogenated C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, halogen, or combinationsthereof, aryl having 6 to 14 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, C₁₋₄ alkylamino,di-C₁₋₄-alkylamino, C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy,cyano, —C(O)—NHOH, —C(O)—NH₂, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl,C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, orcombinations thereof, arylalkyl having 7 to 16 carbon atoms, which issubstituted one or more times by halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH,—C(O)—NH₂, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom, which is unsubstituted or substituted one or moretimes by halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl,—C(O)—NHOH, —C(O)—NH₂, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, or combinations thereof, heteroarylalkyl whereinthe heteroaryl portion has 5 to 10 ring atoms in which at least 1 ringatom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, andthe heteroaryl portion is unsubstituted or substituted one or more timesby halogen, aryl, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, cyano, trifluoromethyl, nitro,amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl,—C(O)—NHOH, —C(O)—NH₂, C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl,C₁₋₄-alkylsulphonyl, or combinations thereof, heterocycle having 5 to 10ring atoms in which at least 1 ring atom is a heteroatom, which isunsubstituted or is substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof,heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atomsin which at least 1 ring atom is a heteroatom and the alkyl portion has1 to 3 carbon atoms, the heterocycle portion is nonaromatic and isunsubstituted or is substituted one or more times by halogen, aryl, C₁₋₄alkyl, halogenated C₁₋₄ alkyl, hydroxy, C₁₋₄-alkoxy, halogenated C₁₋₄alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁₋₄-alkylamino,di-C₁₋₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof, orcarbocycle which is nonaromatic, monocyclic or bicyclic, group having 5to 14 carbon atoms, which is unsubstituted or is substituted one or moretimes by halogen, C₁₋₄ alkyl, halogenated C₁₋₄ alkyl, hydroxy,C₁₋₄-alkoxy, halogenated C₁₋₄ alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, C₁₋₄ alkylamino, di-C₁₋₄-alkylamino,C₁₋₄-hydroxyalkyl, C₁₋₄-hydroxyalkoxy, carboxy, cyano, —C(O)—NHOH,—C(O)—NH₂, C₂₋₄-acyl, C₂₋₄-alkoxycarbonyl, C₁₋₄-alkylthio,C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, phenoxy, or combinationsthereof.
 52. A compound according to claim 1, wherein when R¹ iscyclopropyl, R² is not arylalkyl.
 53. A compound according to claim 49,wherein when R¹ is cyclopropyl, R² is not arylalkyl.
 54. A compoundaccording to claim 50, wherein when R¹ is cyclopropyl, R² is notarylalkyl.
 55. A compound according to claim 51, wherein when R¹ iscyclopropyl, R² is not arylalkyl.
 56. A compound according to claim 1,wherein R¹ is alkyl having 1 to 5 carbon atoms, which is substituted oneor more times by halogen, hydroxy, or combinations thereof, cycloalkylhaving 3 to 6 carbon atoms, or cycloalkylalkyl having 4 to 7 carbonatoms.
 57. A compound according to claim 49, wherein R¹ is alkyl having1 to 5 carbon atoms, which is substituted one or more times by halogen,hydroxy, or combinations thereof, cycloalkyl having 3 to 6 carbon atoms,or cycloalkylalkyl having 4 to 7 carbon atoms.
 58. A compound accordingto claim 50, wherein R¹ is cycloalkyl having 3 to 6 carbon atoms, orcycloalkylalkyl having 4 to 7 carbon atoms.
 59. A compound according toclaim 51, wherein R¹ is alkyl having 1 to 5 carbon atoms, which issubstituted one or more times by halogen, hydroxy, or combinationsthereof, cycloalkyl having 3 to 6 carbon atoms, or cycloalkylalkylhaving 4 to 7 carbon atoms.
 60. A compound according to claim 52,wherein R¹ is alkyl having 1 to 5 carbon atoms, which is substituted oneor more times by halogen, hydroxy, or combinations thereof, cycloalkylhaving 3 to 6 carbon atoms, or cycloalkylalkyl having 4 to 7 carbonatoms.
 61. A compound according to claim 53, wherein R¹ is alkyl having1 to 5 carbon atoms, which is substituted one or more times by halogen,hydroxy, or combinations thereof, cycloalkyl having 3 to 6 carbon atoms,or cycloalkylalkyl having 4 to 7 carbon atoms.
 62. A compound accordingto claim 54, wherein R¹ is alkyl having 1 to 5 carbon atoms, which issubstituted one or more times by halogen, hydroxy, or combinationsthereof, cycloalkyl having 3 to 6 carbon atoms, or cycloalkylalkylhaving 4 to 7 carbon atoms.
 63. A compound according to claim 55,wherein R¹ is alkyl having 1 to 5 carbon atoms, which is substituted oneor more times by halogen, hydroxy, or combinations thereof, cycloalkylhaving 3 to 6 carbon atoms, or cycloalkylalkyl having 4 to 7 carbonatoms.
 64. A pharmaceutical composition comprising a compound accordingto claim 32 and a pharmaceutically acceptable carrier.
 65. Apharmaceutical composition comprising a compound according to claim 33and a pharmaceutically acceptable carrier.
 66. A pharmaceuticalcomposition comprising a compound according to claim 34 and apharmaceutically acceptable carrier.
 67. A pharmaceutical compositioncomprising a compound according to claim 35 and a pharmaceuticallyacceptable carrier.
 68. A compound according to claim 1, wherein R² iscycloalkylalkyl wherein the cycloalkyl portion is cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, norbornyl,1-decalin, adamant-1-yl, or adamant-2-yl.